Massachusetts Route 43 begins at the eastern end of New York State Route 43 in Hancock.

It turns northward through the Kinderhook Creek valley in the Taconic Mountains, passing near Jiminy Peak, and passing through the northern half of Hancock before entering Williamstown.

In Williamstown, the road continues north-northeastward, and crosses U.S. Route 7 in the southern part of town.

After crossing U.S. 7, the road turns right onto Green River Road, which follows its namesake (a tributary of the Hoosac River) around the south and east sides of Stone Hill, before ending at Route 2 just east of the Williams College campus.

The entire route is in Berkshire County.