From Mercersburg, PA 75 heads north and crosses US 30 in Fort Loudon before it runs northeast through a long valley, where it has an interchange with the Pennsylvania Turnpike (Interstate 76 or I-76) in Willow Hill.

PA 75 was designated in 1928 to run from US 30 in Fort Loudon north to US 22 (William Penn Highway) northeast of Port Royal.

PA 75 begins at the Maryland border in Montgomery Township, Franklin County, where the road continues south into that state as MD 494.

From the state line, the route heads north on two-lane undivided Fort Loudon Road through open agricultural areas with occasional homes.

The road turns northwest to run a short distance east of the West Branch Conococheague Creek before coming to an intersection with US 30 near Fort Loudon.

Farther to the northeast, the agricultural valley widens and the route runs through Fannettsburg and Springtown before coming to a ramp providing access to I-76 (Pennsylvania Turnpike).

The road heads into a mix of farmland and woodland with some homes and turns north at Doylesburg, coming to a junction with the western terminus of PA 274.

Farther northeast, the road heads into Tuscarora Township and runs through the residential community of East Waterford before passing through more farmland.

The road continues between farmland to the northwest and forested Tuscarora Mountain to the southeast before turning north into open agricultural areas and heading into Spruce Hill Township.

[2][4] The route continues into Turbett Township and intersects the northern terminus of PA 74, heading through more farmland and woodland with some homes.

Upon designation, the route was paved between north of Richmond Furnace and PA 35 in Blairs Mills and between southwest of Port Royal and US 22 while the remainder was unpaved.

[6] By 1930, the route was paved south from Richmond Furnace to US 30 while the section between Pleasant View and southwest of Port Royal was under construction.