Interstate 376 (I-376) is a major auxiliary route of the Interstate Highway System in the U.S. state of Pennsylvania, located entirely within the Allegheny Plateau. It runs from I-80 near Sharon south and east to a junction with the Pennsylvania Turnpike (I-76, its parent) in Monroeville, after having crossed the Turnpike at an interchange earlier in its route. The route serves Pittsburgh, Pennsylvania and its surrounding areas, and is the main access road to Pittsburgh International Airport (PIT). Within Allegheny County, the route runs along the majority of the Penn-Lincoln Parkway, known locally as the Parkway West and the Parkway East. The route is also known by several other names in various jurisdictions. It is currently the fifth-longest auxiliary Interstate route in the system, and second only to I-476 within the Commonwealth of Pennsylvania.

I-376 is signed east–west despite running north–south for nearly three-quarters of its length; however, it does run east–west through the majority of Allegheny County. This is due to the fact that when the route was first conceived, it was an east–west highway that only connected I-279 in Downtown Pittsburgh to the Turnpike in Monroeville. Despite the route's direction, it serves as a major artery through Pittsburgh's West End, with I-79 being the primary route through Pittsburgh's North Hills. Since its 2009 extension, the route has also served as access to Youngstown, Ohio (through both I-76 & I-80) and, ultimately, Akron, Ohio via I-76, Columbus, Ohio via I-76 & I-71, and Cleveland via I-80.

A 16-mile (26 km) stretch, from exit 15 where I-376 ends its brief concurrency with U.S. Route 422 (US 422) to exit 31 where I-376 has its first intersection with Pennsylvania Route 51 (PA 51), is tolled and is maintained by the Pennsylvania Turnpike Commission, while the remainder of the highway is maintained by PennDOT. Near the airport, I-376 also has a business loop route (BL-376).

I-376 begins at a cloverleaf interchange with I-80 located four miles east of Ohio within the Glaciated Allegheny Plateau. From there, it travels in a southern direction, following the former route of PA 60 along the Beaver Valley Expressway. Paralleling Pennsylvania Route 18, I-376 has its first official interchange with that state highway in West Middlesex, though as PA 760 it also meets that same route about a mile west-northwest of where the Interstate designation now begins (at I-80).

I-376 soon meets US 422 and forms an overlap with that highway along the west side of New Castle. After an interchange with US 224 in Union Township, I-376 eastbound widens to three (and eventually four) lanes in preparation of its split from US 422. Southwest of the city in Taylor Township, I-376 finally exits the roadway to the south with two lanes, leaving US 422 to circle around the southern edge of the city with the other two lanes. At this point, I-376 becomes a tolled freeway.

I-376 continues southward, still paralleled by PA 18, with both that road and the Beaver River to the east. Shortly after entering Beaver County near Koppel, the route interchanges with its parent I-76 – the Mainline of the Pennsylvania Turnpike – for the first time. It also has an indirect connection with Pennsylvania Route 351 at this interchange. Around this area, I-376 crosses into the Unglaciated Allegheny Plateau, where it remains for the remainder of its length.

I-376 then passes to the east of West Mayfield and becomes a non-tolled highway again at its first interchange with Pennsylvania Route 51 in Chippewa Township, just west of Beaver Falls. The freeway then weaves through mountainous terrain, interchanging with Pennsylvania Route 68 in Vanport just before crossing the Vanport Bridge over the Ohio River. It then has its second interchange with PA 18 near Kobuta and continues south from there. I-376 passes to the west of Aliquippa before leaving Beaver County and entering Allegheny County.

Approaching Pittsburgh International Airport (PIT), the freeway diverges to the south onto the Southern Expressway, while Business Loop 376 (the former Business Route of PA 60) branches off to the east. I-376 circles around the southern edge of the airport, interchanging with the north edge of the Southern Beltway (Pennsylvania Route 576) at the main entrance to PIT then recombining with BL-376 shortly thereafter.

Now traveling east-southeastward, the route features a recently rebuilt cloverleaf interchange with the Penn-Lincoln Parkway (US 22 and US 30) and Steubenville Pike (now the northern/western terminus of what remains of Pennsylvania Route 60) in Robinson Township. The two U.S. Highways join I-376 here, continuing east-southeastward bearing the Penn-Lincoln Parkway name, and soon reach an interchange with I-79. From that point eastward, along what was known for many years as I-279, the Parkway West freeway (now designated I-376) runs east-southeast through Rosslyn Farms and Carnegie before turning northeast and passing through Green Tree.

Entering the city of Pittsburgh along the former I-279, the Parkway West winds its way northeast to I-376's second interchange with PA 51 at Saw Mill Run Boulevard, which is also part of a spread-out and somewhat confusing series of ramps linking Banksville Road (US 19) and US 19 Truck. This junction, located just before the freeway passes under Mount Washington in the Fort Pitt Tunnel, features the infamous wrong-way concurrency of US 19 Truck. In addition to running concurrent with its parent route the wrong way, US 19 Truck is wrong-way concurrent onto itself, with both north and southbound traffic of US 19 Truck briefly running on I-376 eastbound.

At the northeastern portal of the tunnel, I-376 emerges onto the double-deck Fort Pitt Bridge, crossing over the Monongahela River. There are single-lane westbound exit and eastbound entrance ramps connecting Carson Street to the freeway between the tunnel's portal and the bridge. Once across the river, the route touches down in Downtown Pittsburgh at the famous Golden Triangle in Point State Park. Here, the now-truncated I-279 begins, branching off to cross the twin Fort Duquesne Bridge and heading out through the North Side to eventually meet up with its parent Interstate. From this same complex interchange, which also includes access ramps for Liberty Avenue, the I-376/US 22/US 30 freeway (named the Penn-Lincoln Parkway East from this point on) turns east to follow the left upstream bank of the Monongahela River through the south side of the downtown area - as well that of as its adjacent neighborhoods, Soho and Oakland. The Parkway East eventually turns away from the river near the southwestern corner of Schenley Park and runs along that park's southern border before passing through Squirrel Hill Tunnel under Squirrel Hill.

Exiting the city of Pittsburgh near the southeastern corner of Frick Park, US 30 leaves the Parkway East freeway shortly thereafter at Pennsylvania Route 8 in the suburb of Wilkinsburg. I-376 continues a general easterly stretch through Churchill, Wilkins Township, Penn Hills, and finally Monroeville, where it eventually meets the toll plaza of the Pittsburgh Interchange leading back onto the Pennsylvania Turnpike's mainline. Just before that plaza, US 22 exits the freeway as well, joining the William Penn Highway (its original routing prior to the construction of the Penn-Lincoln Parkway). I-376 then finally reaches its eastern terminus, at its parent I-76.

The first section of what would eventually become I-376 opened June 5, 1953, from PA 885 (Bates Street) near the Hot Metal Bridge east through the Squirrel Hill Tunnel to US 22 Business (then US 22) at Churchill. The next section to open, running from PA 60 (Steubenville Pike, then US 22/US 30) near Pittsburgh International Airport east to Saw Mill Run Boulevard (PA 51 and US 19), opened October 15, 1953. At Steubenville Pike, it connected to PA 60—the Airport Parkway—which had been built ca. 1950 as a high-speed surface road to provide access to the airport.

In late 1956, it opened from the Boulevard of the Allies (then US 22/US 30) near the Birmingham Bridge east to Bates Street, with the eastbound lanes opening September 10 and westbound opening September 29. The other downtown sections opened in 1958 and 1959. The Fort Pitt Bridge opened June 19, 1959, followed by the Fort Pitt Tunnel on September 1, 1960, using the West End Bypass (Pennsylvania Route 51) and Carson Street (Pennsylvania Route 837) as detours until the Fort Pitt Tunnel opened. The extension east to the Pennsylvania Turnpike in Monroeville opened October 27, 1962. The final piece, from PA 60 west to the US 22/US 30 split at Imperial, opened in 1964. Early plans for that section would have instead taken it from PA 60 where it splits with PA Route 60 Business northwest to US 30 near Campmeeting Road at Clinton.

The next section that opened was in 1968 from the present-day exit 2 with PA 18 and where PA 18 intersects with the present-day PA 760 just north of I-80 and the western terminus of I-376.

Work began on the Beaver County sections of I-376 (in between Chippewa Township and the Airport Parkway) in 1971 and would finish by 1976. The following year, the northern section finished construction, which would leave a gap between New Castle and Chippewa Township for the next 15 years. Until the middle section was completed, in order to continue on the highway, travelers had to use US 422, PA 168, PA 18, PA 251, and PA 51 before returning to the highway. Until that section opened, the present-day exit 12A marked the southern terminus of the northern section of PA 60 as an "END 60" sign was located near the exit.

The next leg of the route opened to PA 108 in 1991 and to PA 51 in Chippewa in 1992 as the "missing link" between two sections of PA 60, when that route's designation was on the highway. The aforementioned "END 60" sign was removed when the first leg of the middle section opened in 1991, and a "No re-entry this exit" sign has sat on the site since, due to exit 12A being an indirect connection to US 422 westbound without a direct re-entry ramp.

The Southern Expressway, which opened in 1992, is the newest portion of I-376, and also has the distinction of being the last freeway to open in the Pittsburgh area that was not a toll road.

The PTC retrofitted E-ZPass lanes on the tolled section of I-376 in 2006 at both the two mainline toll plazas as well as the exits that collect tolls. The 2012 cash toll rates for passenger cars are $.90 at the exits & the Mainline East Toll Plaza 30, and $1.60 at the Mainline West Toll Plaza 18; E-ZPass users pay $1.33 at the Mainline West Toll Plaza 18 and $.67 for the remaining toll booths. As part of Act 44, tolls are to be increased every year on January 1.

From I-376's eastern terminus until the end of the Penn-Lincoln Parkway, I-376 has had the US 22 and US 30 designations for its entire history. Until 1961, it also carried the PA 80 designation until that route was decommissioned due to Pennsylvania needing the designation for I-80 to the north. In 1956, Pennsylvania Route 60 was commissioned to have the Airport Parkway and the former alignment of U.S. 22 & U.S. 30 to Pittsburgh's West End.

From 1959 to 1964, I-70 occupied the highway east of PA 50 in Carnegie. When I-70 moved to its current alignment (replacing I-70S) in 1964, the route received the Interstate 76 designation into Pittsburgh. West of Pittsburgh, from 1963 to 1970, I-79 occupied the route. In West Middlesex, the route would receive the PA 18 designation while the former alignment would receive a business route designation as PA 18 Business, since it served as a bypass of West Middlesex.

In 1970, I-79 swapped positions with I-279, necessitating that I-76 be extended to I-79. With commencement on the Beaver Valley Expressway in 1971, PA 60 was extended to its future northern terminus in Chippewa. Finally, in 1972, after I-76 west of Monroeville moved to the Pennsylvania Turnpike and replaced I-80S, the western part of the highway took the I-279 designation while the section from Pittsburgh east to Monroeville would become the first section with the I-376 designation. When I-376 was extended onto the Parkway West in 2009, I-279 was truncated to its current southern terminus at the former western terminus of I-376.

PA 18 Business was decommissioned in 1978 when PA 18 returned to its former alignment (where it has remained to this day) when PA 60 was extended all the way to Hermitage.

When the James E. Ross Highway started opening in 1991, it would receive the "Toll 60" designation, due to it being operated by the Pennsylvania Turnpike Commission. With the opening of the Southern Expressway in 1992, PA 60 moved to that highway, while the Airport Parkway received the PA 60 Business designation. PA 60 was eventually extended to Sharon in 1997, ending at US 62 Business.

As part of the Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users in 2005, the U.S. Congress had designated an expansion of I-376 past I-79 and along present day US 22/US 30 and PA 60 through the Pittsburgh International Airport and north to I-80 near Sharon, Pennsylvania. This was done because the Airport held the dubious distinction of being the only major airport in the United States without direct access to an Interstate highway.

This routing required some major infrastructure work on US 22 west of Downtown Pittsburgh (particularly at the US 22/US 30 cloverleaf in Robinson Township) and safety improvements to PA 60; though both were limited access freeways before the extension, they were not up to Interstate Highway standards in all areas. The improvements to both the US 22/US 30 cloverleaf in Robinson Township and the Lawrence County leg of the route, as well as replacing all of the signs with the I-376 shield, were funded by the American Recovery and Reinvestment Act of 2009.

The designation of I-279 from Downtown west through the Fort Pitt Tunnel to I-79 was officially dropped and replaced by that of I-376 on June 10, 2009. I-279 still exists between I-376 in the Golden Triangle and I-79 in Franklin Park. On November 6, 2009, officials announced the initial transition was complete.

On January 21, 2010, the remainder of the route except for the James E. Ross highway started receiving the I-376 signs. The stretch of PA 60 from I-80 in Shenango Township of Mercer County north past PA 18 (where the freeway terminates and the highway reverts to being a two lane arterial) to the former northern terminus of PA 60 in Sharon became PA 760.

On August 1, 2010, signage along Turnpike 60 was officially changed to I-376, and unlike other tolled highways with Interstate designation it is not grandfathered from Interstate standards. Having been built in the early 1990s, this section was already up to Interstate standards. This section of I-376 is signed as "Toll I-376", with a black-on-yellow "Toll" sign above the I-376 trailblazer. This makes I-376 one of the first tolled Interstates with such a marker, which was a new addition to the 2009 edition of the Manual on Uniform Traffic Control Devices.

Despite PennDOT giving motorists over four years of advance notice on the I-376 extension, some local drivers were confused after the transition was complete, thinking that the I-376 extension was going to be an all-new highway instead of a renaming of PA 60.

In 2012, PennDOT accepted an Adopt a Highway sponsorship along much of I-376 in Pittsburgh from a local strip club located in Downtown Pittsburgh, with signs about the sponsorship located throughout the Penn-Lincoln Parkway. According to PennDOT officials, strip clubs are permitted, along with any other business, to sponsor such projects, since it keeps the roads clean and saves taxpayers money. Despite the sponsorship, the program does not send strippers to clean the roads, but rather sends workers from the state paid for by the club to clean the highways.

Business Loop 376 (BL-376), known locally as the Airport Parkway, is a six-mile (9.7 km) Interstate Highway business loop in Moon Township and Findlay Township, Pennsylvania. Its western terminus is at I-376 and Flaugherty Run Road (exits 50 and 51) north of Pittsburgh International Airport (PIT). Its eastern terminus is at I-376's exit 57, southeast of PIT.

Before November 6, 2009, and after the Southern Expressway was completed in 1992, this road was known as Pennsylvania Route 60 Business. Prior to that, this route had the regular PA 60 designation. Much of the road is up to freeway standards, but several signaled at-grade intersections remain, making this multi-lane divided road a true expressway (unlike many of Pennsylvania's freeways, which are often misleadingly named using the suffix expressway, since they are often called such in the northeast). Along with the business loop of Interstate 83 in York, Pennsylvania, BL-376 is one of only two business Interstate routes found in the Commonwealth of Pennsylvania.