The state highway, which is a two-lane undivided road its entire length, runs 2.384 miles (3.837 km) from the Maryland state line, where the highway continues south as Maryland Route 63 (MD 63), east to U.S. Route 11 (US 11) in Antrim Township in southern Franklin County.

PA 163 runs immediately to the north of the state line along Mason Dixon Road, coming to an interchange at Interstate 81 (I-81) before ending at US 11.

PA 163 begins heading north from the state line on two-lane undivided Williamsport Pike, then immediately turns east onto Mason Dixon Road.

The distance reduces to less than 50 feet (15 m) after the state highway crosses Norfolk Southern Railway's Lurgan Branch at-grade.

PA 163 continues east through farmland, intersecting Maugansville Road on the Maryland side before reaching its interchange with I-81 (American Legion Memorial Highway).