In southwest Ohio, it overlaps with State Route 3 (SR 3) and is familiarly known as the 3-C Highway, "22 and 3", and Montgomery Road.

A section of US 22 in Pennsylvania between New Alexandria at US 119 and Harrisburg at Interstate 81 (I-81) has been designated a part of Corridor M of the Appalachian Development Highway System.

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.

US 22 enters Pennsylvania as a limited-access highway connecting Weirton, West Virginia, and Steubenville, Ohio, with Pittsburgh.

Near Mount Union, it forms a concurrency with US 522, and the two highways go northeast along the Juniata River to Lewistown.

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.

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.

[7][8] Before the Byrd Expressway, West Virginia's segment of US 22 ran from Pennsylvania Avenue at the West Virginia–Pennsylvania state line to Main Street, then left on Main Street through downtown Weirton (aligning US 22 with WV 2), and right on Freedom Way to the Fort Steuben Bridge and Ohio River to Steubenville, Ohio.

[citation needed] With the opening of the first segment of the Byrd Expressway on March 9, 1972,[9] US 22 was reassigned, starting on the new road from the West Virginia–Pennsylvania state line, continuing on Cove Road where the expressway ended and joining the remainder of the original route at Main Street.

In 2003, WV 507 was extended along the previous US 22 alignment from Cove Road to the Fort Steuben Bridge and was reassigned as CR 507.