NY 378 progresses southeast as Menand Road, a two-lane residential street through Colonie.

The road expands to four lanes before intersecting with the northern terminus of NY 377 (Van Rennselaer Boulevard).

After this intersection, NY 378 becomes a four-lane freeway, crossing eastbound through Colonie and into Menands.

The route turns to the northeast, passing to the north of Ganser-Smith Memorial Park, crosses over a railroad line via a bridge, before entering into an interchange with NY 32 (Broadway).

NY 378 goes back to four lanes before crossing the Hudson River on the Menands Bridge, entering the city of Troy.