From Watertown eastward, Route 16 is a multi-lane arterial road, although it is not limited access for any significant length.

After passing I-395, the route continues to the northeast, going through Douglas (with a trip through the Douglas State Forest), the Blackstone River Valley National Heritage Corridor, Uxbridge, Mendon, Hopedale, and Milford, where it crosses the Charles River and then passes beneath I-495 {without access}.

From I-495, Route 16 goes northeasterly past Holliston and the Elm Bank Reservation in Sherborn.

Entering Newton, the route travels past Lasell College while crossing into Middlesex County.

It soon is joined from the north by Massachusetts Route 38, and shortly after enters a mile long freeway segment, bypassing downtown Medford (after recrossing the river), where Route 38 exits to the south on Main Street.

This junction marks the end of the Mystic Valley Parkway and the beginning of the Revere Beach Parkway, on which Route 16 continues eastward, passing the Wellington MBTA station and crossing the Malden River.