U.S. Route 22 (US 22) is a west–east route and is one of the original United States highways of 1926, running from Cincinnati, Ohio, at US 27, US 42, US 127, and US 52 to Newark, New Jersey, at U.S. Route 1/9 in the Newark Airport Interchange. US 22 also carries the names of the William Penn Highway throughout most of Pennsylvania. In southwest Ohio, it overlaps with Ohio State Route 3 and is familiarly known as the 3C Highway, "22 and 3", and Montgomery Road.

A section of US 22 between New Alexandria at U.S. Route 119 and Harrisburg at Interstate 81 has been designated a part of Corridor M of the Appalachian Development Highway System.

In Ohio, US 22 between Zanesville and Lancaster roughly follows the route of Zane's Trace, an early pioneer road blazed by Colonel Ebenezer Zane beginning in 1796. From Cincinnati to Washington Court House, US 22 roughly follows the historic 3C Highway which connected Cincinnati, Columbus, and Cleveland. This section is also contiguous with Ohio State Route 3. Both US 22 and State Route 3 end in downtown Cincinnati; officially, US 22 Eastbound begins on Central Avenue (U.S. Routes 27 Northbound/52 Westbound/127 Northbound) at 5th Street, then proceeds north, turning east onto 7th Street, while U.S. 22 Westbound follows 9th Street and ends at Central Avenue (signage designating the end occurs much sooner, approaching Elm Street, U.S. Route 42 Northbound).

Known as the Robert C. Byrd Expressway, the expressway passes for approximately five miles within the state of West Virginia, through or bordering the city of Weirton for its entire length, from the Pennsylvania state line on the east to the Ohio River and Steubenville, Ohio on the west.

Before the Byrd Expressway, West Virginia's segment of U.S. 22 ran from Pennsylvania Ave. at the PA/WV state line to Main St., then left on Main St. through downtown Weirton (aligning U.S. 22 with West Virginia Route 2), and right on Freedom Way to the Fort Steuben Bridge and Ohio River to Steubenville, Ohio. An "Alternate U.S. 22" route ran along Cove Rd. from Pennsylvania Ave. to the intersection of Harmon Creek Rd. (left turn) and the continuation of Cove Rd. (right turn).

With the opening of the first segment of the Byrd Expressway in the mid-1970s, U.S. 22 was reassigned, starting on the new road from the PA/WV state line, continuing on Cove Rd. where the expressway ended and joining the remainder of the original route at Main St. The Pennsylvania Ave. segment of U.S. 22 from Colliers Way to Main St. was reassigned as WV Route 105 and Alt. U.S. 22 was reassigned as WV Route 507. In 2003, WV 507 was extended along the previous U.S. 22 alignment from Cove Rd. to the Fort Steuben Bridge and was reassigned as County Route 507. The Fort Steuben Bridge, which originally carried U.S. 22 across the Ohio River until the construction of the Veterans Memorial Bridge, was permanently closed on January 8, 2009, and demolished by detonation on February 21, 2012.

US 22 enters Pennsylvania as a limited-access highway connecting Weirton, WV and Steubenville, OH with Pittsburgh. Through much of the Pittsburgh area, it multiplexes with Interstate 376 and US 30. US 30 merges with US 22 near Imperial and Pittsburgh International Airport, and both highways then merge with Interstate 376 in Robinson Township. Together, these three highways form a busy, limited-access multiplex through the city of Pittsburgh. US 30 then splits from Interstate 376 and US 22 in Wilkinsburg, and Interstate 376 ends at the Pennsylvania Turnpike (Interstate 76) in Monroeville. East of Interstate 376, US 22 continues east as a primary arterial highway between Pittsburgh and major population centers in central Pennsylvania, such as Johnstown, Altoona, State College, Huntingdon, and Lewistown. The entire length between Pittsburgh and Interstate 99 just west of Altoona was widened to at least four lanes by summer 2011.

US 22 between eight miles (13 km) east of Interstate 81 to Allentown is concurrent with Interstate 78. Former highway alignments of US 22 that parallel this section are collectively known as the "Hex Highway", so called because of the Berks County-based Pennsylvania Dutch families that hang hex signs on their barns.

US 22 in eastern Pennsylvania is a four lane limited-access expressway between Easton and Interstate 78 to the west; it is dually designated with the Lehigh Valley Thruway in Allentown. The original designation for this expressway was to be Interstate 78, but local opposition to a freeway in Phillipsburg, along with substandard conditions at Easton, forced federal highway officials to relocate Interstate 78 south of Allentown, Bethlehem, Easton, and Phillipsburg. U.S. 22 then crosses the Delaware River on the Easton–Phillipsburg Toll Bridge.

U.S. Route 22 in New Jersey predates, and was largely replaced by, Interstate 78 as it was built between 1956 and 1989, and shares designation with I-78 from exit 3 to exit 18. US 22 was an expressway in some segments, including the area around Perryville and Clinton. It connects Phillipsburg with Newark in New Jersey.

US 22 has one major interchange besides I-78, that being Interstate 287, although it is not a full interchange, with two missing movements, US 22 eastbound to I-287 northbound and I-287 southbound to US 22 westbound.

The only level crossing of the highway happens in Union County in the Union Township section of the highway. It once belonged to the Rahway Valley Railroad; the crossing was closed in 1992 when service on the railroad was ended.

US 22 is one of the original U.S. Routes, though in the 1925 plan it was to terminate in Cleveland, Ohio, entering Ohio on modern U.S. Route 422. In the finalized 1926 plan, it followed the current course to U.S. Route 40, where it ended. In 1932, it had been extended to Cincinnati as it is currently, replacing Ohio State Route 10 and following preexisting State Route 3.