The highway runs 5.0 miles (8.0 km) from SR 42 in Harrisonburg east to U.S. Route 33 (US 33) in Massanetta Springs in central Rockingham County.

The state highway continues southeast as Stone Spring Road, which crosses over Black Run and the Harrisonburg–Pleasant Valley rail line of the Chesapeake Western Railway.

SR 280 leaves the city limits of Harrisonburg and enters unincorporated Rockingham County shortly after it crosses over I-81 with no access.

The highway curves east before its junction with SR 253 (Port Republic Road).

SR 280 continues east through the unincorporated community of Massanetta Springs until it reaches its eastern terminus at US 33 (Spotswood Trail) south of Harrisonburg.