U.S. Route 40 is Maryland's longest numbered highway; it runs 220 miles from the Pennsylvania line near Keysers Ridge in Garrett County to the Delaware line near Elkton in Cecil County via Hagerstown, Frederick, Ellicott City and Baltimore. Considerable lengths of US 40 in Maryland run concurrent with interstates 68 and 70. Part of US 40 in west Baltimore uses the never-completed Interstate 170.

US 40 has a scenic route between Cumberland and Hancock, an alternate route between Hagerstown and Frederick, and an unsigned truck route in Baltimore which uses Hilton Parkway, North Avenue, Belair Road and Erdman Avenue.