US 322 begins at the intersection of Superior Avenue and East Roadway at Public Square in Downtown Cleveland, just northeast of the junction of U.S.

[3][4] East of Public Square, the route runs eastward through midtown Cleveland conjoined with US 6 along Superior Avenue.

Northwest of Cleveland State University, US 322 turns south onto 13th Street and runs eastward (as Chester Avenue) through Playhouse Square.

At the interchange between I-83 and the northern terminus of Interstate 283, US 322 turns east and heads to Hershey, intersecting U.S. Route 422.

From this point, US 322 heads southeast through the Pennsylvania Dutch Country, intersecting U.S. Route 222 at a diverging diamond interchange near Ephrata.

Here, US 322 bypasses the town and merges onto a freeway alignment along with U.S. Route 202 that ends to the south of West Chester.

In the 1960s and 1970s, the New Jersey Department of Transportation (NJDOT) had planned for a freeway bypass of U.S. Route 322 around Glassboro.