Ohio

US 22 has its westernmost endpoint in downtown Cincinnati. Its eastbound and westbound endpoints are not at the same intersection. Officially, US 22 eastbound begins on Central Avenue (US 27 northbound/US 52 westbound/US 127 northbound) at 5th Street, then proceeds north, turning east onto 7th Street. Meanwhile, US 22 westbound follows 9th Street and officially ends at Central Avenue^[4] (signage designating the end occurs much sooner, approaching Elm Street, US 42 northbound).^[5]

From downtown Cincinnati to Washington Court House, US 22 roughly follows the historic 3-C Highway which connected Cincinnati, Columbus, and Cleveland. This section is also concurrent with SR 3. At Washington Court House, SR 3 and US 22 diverge. US 22 continues to the east through Circleville to Lancaster. From Lancaster to Zanesville, US 22 roughly follows the route of Zane's Trace, an early pioneer road blazed by Ebenezer Zane beginning in 1796.

Starting just west of Cadiz, US 22 becomes a limited-access expressway for the remainder of its approximately 30 miles (48 km) in Ohio as it approaches and enters Greater Pittsburgh (with the exception of an at-grade intersection with no stoplights or signs on US 22 and narrowing to two lanes for about a mile (1.6 km) east of Cadiz). It junctions with SR 7 for roughly a mile (1.6 km) along the Ohio River shoreline in Steubenville.

West Virginia

Known as the Robert C. Byrd Expressway, the expressway route that began roughly 30 miles (48 km) to the west near Cadiz, Ohio, continues for approximately five miles (8.0 km) within the state of West Virginia (the highway runs concurrent with West Virginia Route 2, or WV 2, for one of those miles, or 1.6 km) as it approaches more population density within Greater Pittsburgh. US 22 travels through or borders the city of Weirton for its entire length in West Virginia, from the Ohio state line over the Ohio River, to the Pennsylvania state line.

Pennsylvania

US 22 enters Pennsylvania as a limited-access highway connecting Weirton, West Virginia, and Steubenville, Ohio, with Pittsburgh. Through much of Greater Pittsburgh, it overlaps I-376 and US 30. US 30 merges with US 22 near Imperial and Pittsburgh International Airport, and both highways then merge with I-376 in Robinson Township. Together, these three highways form a busy, limited-access multiplex through the city of Pittsburgh. US 30 then splits from I-376 and US 22 in Wilkinsburg, and the I-376/US 22 concurrency continues to the Pennsylvania Turnpike in Monroeville, where I-376 ends.

East of I-376, US 22 continues east of Pittsburgh as a primary arterial highway. The entire length between Pittsburgh and US 220 and I-99 just west of Altoona was widened to at least four lanes by mid-2011. I-99 links the highway to State College and the Pennsylvania Turnpike. Heading east from I-99, US 22 narrows and becomes the primary highway linking Hollidaysburg and Huntingdon. Near Mount Union, it forms a concurrency with US 522, and the two highways go northeast along the Juniata River to Lewistown.

In Lewistown, US 22 breaks with US 522 and forms a concurrency with US 322, and the two routes travel southeast, mostly as an expressway, toward Harrisburg. At the north end of Harrisburg, US 22 and US 322 split and US 22 runs southward toward the Pennsylvania Farm Show Complex & Expo Center. From there, it turns eastward along Arsenal Boulevard, Herr Street, and Walnut Street to Jonestown Road. Through Dauphin and Lebanon counties, US 22 parallels I-81 and I-78 to the south as a four-lane arterial. East of Fredericksburg, along the border between Lebanon and Berks counties, US 22 forms a concurrency with I-78, which runs to the Allentown area. 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.

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

New Jersey

US 22 in New Jersey predates and was largely replaced by I-78 after I-78 was built between 1956 and 1989^[6] 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 I-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.

One of two level crossing of the highway happens in Union County in the Union Township section of the highway (the other occurring in Lewistown, Pennsylvania). It once belonged to the Rahway Valley Railroad; the crossing was closed in 1992 when service on the railroad was ended.