Route 146 begins in Branford as Main Street, splitting off from West Main Street (US 1) just east of the Branford Connector, which connects to I-95 south.

At Pine Orchard, Route 146 turns north onto Blackstone Avenue and Totoket Road.

Leetes Island Road crosses into the town of Guilford, bears north briefly on Sachem Head Road, then northeast onto Water Street, passing on the south side of the Guilford Town Green as Boston Street, eventually terminating at US 1 east of the town center.

In 1962, Route 146 took over former Route 143 (road to Indian Neck and Pine Orchard) and former SR 445 (South Main Street), ending at US 1A (Main Street).

The following year, US 1A was decommissioned in Branford, and Main Street became part of Route 146.