The western terminus of the route is at Interstate 579 in downtown Pittsburgh near PPG Paints Arena.

PA 380 begins along the ramps of the Bigelow Boulevard and Interstate 579 interchange in Downtown Pittsburgh, north of the former Civic Arena complex.

The route proceeds east traversing Ammon Playground park in the Hill District.

PA 380 also parallels Norfolk Southern's Pittsburgh Line and the PRT's Martin Luther King Jr. East Busway on this section of the four-lane Bigelow Boulevard.

Near the Alcoma Golf Club, PA 380 leaves the Yellow Belt, while turning east onto Saltsburg Road.

Roughly east of the Pennsylvania Turnpike overpass in the borough of Plum, PA 380 begins an overlap with the Orange Belt at the intersection with Center Road near Boyce Park.

[7] In the late 1920s and early 1930s, PA 380 was first designated from Pennsylvania Route 80 in Murrysville to the current eastern terminus.