The 36-mile (58 km) section between its splits from I-95 in East Lyme and SR 695 in Plainfield is a component highway of the Connecticut Turnpike.

[2] I-395 begins at the East Lyme–Waterford town line as the Connecticut Turnpike leaves I-95 as the latter route turns more easterly toward New London.

[3] After passing through Webster and Oxford, it enters Auburn where it has an interchange with US 20, which provides access to the Route 146 expressway.

The I-395 designation for the highway ends as it meets I-90 (Massachusetts Turnpike) at exits 11A and 11B and becomes I-290 as it heads toward Worcester, although the mileage for I-395 runs in parallel with its I-290 counterpart until it reaches I-495 in Marlborough.

In Connecticut, there are three service plazas (a legacy of the turnpike) that provide 24-hour gas stations, convenience stores, plus a Subway and Dunkin' Donuts.

The Connecticut State Police Troop E barracks occupies the former service plaza on the northbound side at Montville.

The highway that is now I-395 from its southern terminus with I-95 in East Lyme to exit 35 in Plainfield opened on January 2, 1958, as part of the 129-mile (208 km) Connecticut Turnpike from Greenwich at the New York state line to Killingly at the Rhode Island state line.