The south end of SR 100 is at the intersection of Forest Avenue and Cumberland Avenue in downtown Portland.

The majority of SR 100 is concurrent with other routes: US 302 from downtown Portland to northern Portland, SR 26 from northern Portland to Gray, US 202 from Gray to Augusta, US 201 from Augusta to Fairfield, SR 11 from Fairfield to Newport, and US 2 from Newport to downtown Bangor.

The only parts of SR 100 that do not run along another route are in Portland, first (as Forest Avenue) between its southern terminus and the Interstate 295/US 1 interchange (where US 302 begins) and between US 302 and SR 26 where it is alone on a small piece of Allen Avenue.

[3] State Route 100A (SR 100A) is a 5.2-mile (8.4 km) alternate route of SR 100 running between the towns of Winslow and Benton.

The old alignment, which connected to SR 100 at both ends, was redesignated as SR 100A (as a bypass of SR 100's alignment in Winslow and Benton).