It began at the north end of the Boston University Bridge, which carried US 3 across the Charles River, and ran east on present Memorial Drive and Land Boulevard before turning north on the Northern Artery (present Route 28) to reach present Route 38 at Mystic Avenue.

Between 1945 and 1950, it was extended north from Lowell to cross the Merrimack River on Gorham Street, then its present alignment to the newly formed New Hampshire Route 38.

The present alignment in Lowell was adopted in or after 1954, when the new bridge across the Merrimack River was built.

Later it was shifted north to the Mystic Valley Parkway (Route 16) due to South Street becoming one-way eastbound.

By 1989, Route 38 was moved to a short bypass around the rotary in Winchester center.