U.S. Route 22 is an east–west route stretching from Cincinnati, Ohio in the west to Newark, New Jersey in the east. In Pennsylvania, the route runs for 337.60 miles (543.31 km) between the West Virginia state line at Washington County, where it is a limited-access expressway-grade route through the western suburbs of Pittsburgh, to the New Jersey state line at Easton.

US 22 carries multiple names as it progresses across the state, including the William Penn Highway and the Lehigh Valley Thruway. Several sections of the road are freeway, including the Lehigh Valley Thruway.

US Route 22 crosses into Pennsylvania from West Virginia as the William Penn Highway. It becomes concurrent with US Route 30 and then also with I-376 west of Pittsburgh, and becomes the Penn Lincoln Parkway. It continues as such through Pittsburgh and beyond the end of the US 30 concurrency, and when I-376 reaches its eastern end at the Pennsylvania Turnpike, US 22 goes onto William Penn Highway again. It is also known as the Admiral Peary Highway from Armagh to the Altoona area. From New Florence through most of Ebensburg, US 22 is an expressway with the remaining portion from Ebensburg to Cross Creek operating as a limited-access freeway. From Duncansville to Mount Union, US 22 is a two-lane road with occasional passing and truck-climbing lanes, and it passes through the business district of Huntingdon, where it is three lanes (one lane each way with a turning lane in the middle). It becomes concurrent with US 522 near Mount Union and remains a two-lane road. The US 522 concurrency continues until Lewistown. US 22 bypasses the downtown area of Lewistown as a four-lane limited access highway and becomes concurrent with US 322, continuing as a four-lane limited access highway along the Juniata and Susquehanna rivers until Harrisburg. In Harrisburg (with the US 322 concurrency ending at I-81), it continues as N Cameron Street, Arsenal Blvd., Herr St., Walnut St., Jonestown Rd., and Allentown Blvd. In Fredericksburg, US 22 becomes concurrent with I-78 for a 40-mile (64 km) stretch before splitting off on to the Lehigh Valley Thruway.

The Lehigh Valley Thruway is a 24-mile-long (39 km) freeway portion of US 22 from the eastern end of the Interstate 78/US 22 concurrency in Kuhnsville, west of Allentown, to the state line in Easton. The highway travels just to the north of Allentown and Bethlehem and passes through Easton. Originally, I-78 would have continued with the U.S. 22 concurrency on the Lehigh Valley Thruway into New Jersey, with I-278[citation needed] running south as a bypass, and I-178 and I-378 serving Allentown and Bethlehem respectively. Due to opposition in Phillipsburg, New Jersey on the building of a I-78/U.S. 22 highway through the town (the same opposition that later killed the Somerset Freeway for I-95 in 1982), PennDOT and NJDOT decided to reroute the I-78 highway onto the proposed I-278 bypass and allow U.S. 22 to remain on the limited-access highway, which, after going through sharp curves and crossing the Delaware River into NJ, becomes an at-grade divided highway in Phillipsburg. Traffic on the Lehigh Valley Thruway is often heavy at rush hour, particularly near the PA 145 interchange. Once in Easton, the highway goes through a series of potentially dangerous curves, locally known as "Cemetery Curve." For this reason, the speed limit is lowered to 45 mph at Route 248 and then lowered to 35 mph around the sharpest part of the curve. At the interchange with Bushkill Street, US 22 becomes an elevated highway until crossing into New Jersey. The speed limit drops once again to 25 mph while crossing the Easton-Phillipsburg Toll Bridge.

In 2011, it was announced that plans were being resurrected to widen US 22 from Allentown to Bethlehem. Part of the plan is to reconstruct the Lehigh River Bridge. The plan's cost is between $240 to $320 million. Details of the proposed construction can be found on www.22lv.com.

The William Penn Highway was organized as an alternative to the Lincoln Highway being parallel to the Pennsylvania Railroad west of Harrisburg. The route's New York Extension was adopted in 1916. The Pennsylvania Department of Highways assigned the Pennsylvania Route 3 designation to this road in 1924, and in 1926 it became part of U.S. Route 22 when the United States Highway System was formed, The road became problematic for motorists in Lebanon along the current U.S. Route 422; Reading via U.S. Routes 22 and 222; and Allentown on Hamilton Street (US 22). The highway continued through Allentown on Hanover Avenue and through Bethlehem on Broad Street, Linden Street, and Easton Avenue.

Pennsylvania Route 43 was aligned as a bypass, north of the Pennsylvania Dutch Country, that ran from U.S. Route 22, U.S. Route 11, and Pennsylvania Route 5 in Harrisburg to Pennsylvania Route 12 in Bethlehem. The route from Fogelsville to Allentown, now Main Street, Tilghman Street, Broadway, College Heights Boulevard, and Liberty Street, was designated LR 443 in 1925, and was soon incorporated into "Traffic Route 43." The New York Times was recommending use of this cutoff by early 1931. On June 8, 1931, the American Association of State Highway Officials came to a resolution for the traffic problem, by replacing the PA 43 corridor with US 22. The Pennsylvania Department of Highways moved the William Penn Highway name to match. The state truncated PA 43 to Susquehanna Street from Allentown to Bethlehem.

Tilghman Street was eventually connected directly from Cetronia to Allentown by a bridge over Cedar Creek; Tilghman Street (west of the Lehigh River) and Union Boulevard (east of the river) were joined in 1929 by a bridge. By 1936, US 22 had been moved from its Hamilton Street and Broad Street alignment to Tilghman Street and Union Boulevard through Allentown and Bethlehem. When the Lehigh Valley Thruway was completed in 1954, US 22 was moved onto it. With the completion of Interstate 78, US 22 was moved onto that highway from Fredericksburg to Kuhnsville.

Old U.S. Route 22 is the former PA 43, and the earlier version of the newer, more traveled U.S. Highway 22. It starts in the unincorporated community of Bethel, Pennsylvania of Berks County and ends in Cetronia, just outside of the city of Allentown (Lehigh County) where it becomes Main Street and then Tilghman Street. This road, although no longer a major state highway, is well traveled by those who live in the vicinity. It passes through several communities including Shartlesville, Jalappa, West Hamburg, Edenburg, Krumsville, and New Smithville. It also passes through the boroughs of Strausstown, Hamburg and Lenhartsville. Old U.S. Route 22 crosses seven Pennsylvania highways including 501, 419, 183, 61, 143, 737, and 863. Through these different neighborhoods, this road is defined as Old Route 22, Hex Highway, and Shartlesville Road.

From Cetronia east, the old road is State Route 1002 in Lehigh County, comprising Tilghman Street and Union Boulevard in Allentown. In Northampton County, the 1940s highway is Union Boulevard, Linden Street, and Easton Avenue in Bethlehem; William Penn Highway between Bethlehem and Easton; and Butler Street, 13th Street, and Northampton Street in Easton.

U.S. Route 22 Business is a 5-mile loop through the eastern Pittsburgh suburbs of Churchill, Wilkins Township, and Monroeville, Pennsylvania. The route's western terminus is at a freeway junction with Interstate 376, which features cosignment by the business loop's parent route. The first two miles of the road are contained in a valley, surrounded by a variety of side roads leading to suburban, mostly residential development. The remaining three miles feature dense commercial development, including several office high rises and the Monroeville Mall. The highway ends at a complicated junction that features the northern terminus of Pennsylvania Route 48, the southern end of Haymaker Road, and Interstate 376, which features its last two exits (before the Pennsylvania Turnpike) with the above streets. Business US 22 then travels for its final eighth of a mile on a viaduct that allows for connections with the Pennsylvania Turnpike and a smooth transition on to US 22 east toward affluent suburban Murrysville, Pennsylvania.

U.S. Route 22 Business is a 6-mile loop through Lewistown, Pennsylvania. It serves as the major through street, taking on the former designation of its parent, which has become a freeway bypass. The first two miles of the route travel through rural Granville Township. The middle two mile segment is lined with small development and features several stop lights and a segment that contains a center turning lane. The last two miles wind along the Juniata River toward the eastern freeway juncture.