Route 10 crosses the border from Granby, Connecticut into Southwick, Massachusetts, overlapped with U.S. 202.

It runs north through the Pioneer Valley towns of Southwick, Westfield, Southampton, Easthampton, Northampton, Hatfield, Whately, Deerfield, Greenfield, Bernardston, Gill, and Northfield.

Route 10 has a long concurrency with U.S. 5 for about 25 miles (40 km) from Northampton to Bernardston, where it was sometimes called the "5 & 10 Highway".

An odd sight greeted motorists in Easthampton in July 2005: standard issue Alabama state highway signs with the number 10 in a map of that state, instead of the standard Massachusetts square.

This odd "Alabama 10" signage came about when a contractor mistakenly applied the sample from a federal manual.