We start the drive from Marlborough to Amesbury merging onto Interstate 495 at the eastern terminus of Interstate 290 in northwest Marlborough. Driving generally northeast, we pass the interchange with MA-2 near Littleton. Continuing northeast, we pass through Littleton Common and Chelmsford before reaching Lowell at the interchange with U.S. Highway 3.
Passing through the south side of Lowell, we continue our drive northeast to Lawrence where we cross the junction with Interstate 93. Entering Lawrence, we cross interchanges with MA-28 and MA-213 before crossing the Merrimack River to enter Haverhill where we cross MA-125.