The route begins at an intersection with NY 52 in East Fishkill and passes north through Hopewell Junction and Red Oaks Mill on its way to the city of Poughkeepsie.

It ends at a junction with U.S. Route 44 (US 44) and NY 55 east of the city limits in Arlington, a hamlet in the town of Poughkeepsie.

It proceeds north about 1.5 miles (2.4 km), crossing over Fishkill Creek and continuing into the hamlet of Hopewell Junction, where it overlaps with NY 82 for 450 feet (140 m).

NY 376 turns north at this intersection, running along the eastern perimeter of and providing access to the passenger terminal of Dutchess County Airport.

North of the airport, NY 376 runs closely parallel to Wappinger Creek, briefly entering the town limits of La Grange before crossing the Wappinger Creek into the town of Poughkeepsie.

After heading north and northwest for 2.3 miles (3.7 km), NY 376 turns right onto Raymond Avenue at Vassar College.

Additionally, the roundabouts have drawn much controversy from local residents because they remove a lane of traffic in each direction, reducing Raymond Avenue (NY 376) from a four-lane road to a divided two-lane boulevard and significantly altering pre-existing traffic patterns.

[14] In response, NYSDOT installed traffic calming measures on these parallel roads prior to the construction of the Fulton Avenue roundabout.