U.S. Route 22 (US 22) is a west-east route and is one of the original United States highways of 1926. It originally stretched from Cambridge, Ohio, to Elizabeth, New Jersey, however, today it runs from Cincinnati, Ohio, at US 27, US 42, US 127, and US 52 to Newark, New Jersey, at U.S. Route 1/9 near the Newark Liberty International Airport. US 22 also carries the names of the William Penn Highway throughout most of Pennsylvania. In southwest Ohio, it overlaps with OH 3 and is familiarly known as the 3C Highway, "22 and 3", and Montgomery Road.
Old Route 22, also known as Business Route 22, is still a major route through major business districts of Weirton. It includes Pennsylvania Avenue from the Pennsylvania state line west to its intersection with Main Street. Main Street, which is also part of West Virginia Route 2, carries old Route 22 south and west of that intersection to the Ohio River, where motorists have the option of crossing the Veterans Memorial Bridge (also known as the Weirton-Steubenville Bridge, part of the Route 22 expressway) or turning right onto Freedom Way to the old Fort Steuben Bridge to connect to Ohio Route 7 north of Steubenville.
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. It 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 missing movements on US 22 eastbound and I-287 southbound (US 22 eastbound to I-287 northbound and I-287 southbound to US 22 westbound).