SR 101 begins at an intersection with U.S. Route 1 (US 1) in Kittery, and runs northwest to the New Hampshire state line, where it continues as Gulf Road, an unnumbered local road in Dover towards New Hampshire Route 4.

The route heads northwest, intersecting local roads as it passes east of the town of Eliot.

The highway continues a short distance northwest before crossing the Piscataqua River into Dover, New Hampshire.

Motorists following this road west will soon come across signage leading to New Hampshire Route 4 towards downtown Dover.

No advance signage exists in the reverse direction, with Gulf Road simply transitioning to SR 101 upon crossing into Maine.