Route 81 begins at an intersection with US 1 in the town center of Clinton and heads north as Hull Street then quickly shifts to High Street.

It intersects with I-95 (exit 63) about 0.7 miles (1.1 km) north of US 1 and passes in front of the Clinton Crossing outlet mall before heading into the town of Killingworth.

North of I-95 in Clinton, the road is known as Killingworth Turnpike.

North of Route 80, the road becomes known as Higganum Road, intersecting with Route 148 north of the town center before crossing into the town of Haddam.

[1] In the 19th century, the road connecting the villages of Clinton, Killingworth, and Higganum was a private turnpike known as the Killingworth and Haddam Turnpike.