Route 21 is a south–north state highway in Massachusetts that runs between Springfield and Belchertown.

The route begins at U.S. Route 20 in the Indian Orchard section of Springfield. It heads north, intersecting with Route 141 before crossing the Chicopee River into Ludlow. Once in Ludlow, the road continues in a northeasterly direction. It passes under the Massachusetts Turnpike, with access to that road via Exit 7. It continues through town, passing south of the Springfield Reservoir before heading northward into Belchertown. In Belchertown it shares a concurrency with U.S. Route 202, which ends at Route 181. From there Route 21 makes its final short trek to its current terminus at Route 9.

Prior to the completion of the Quabbin Reservoir, Route 21 extended further northward. It passed through the former town of Enfield, then northward along the Swift River into Greenwich and the northern end of Dana before heading through the current town of Petersham and into Athol, where it terminated at what is now Route 2A. The southern portion of the road (Old Enfield Road) is still accessible in Belchertown. The northern trunk follows Pleasant Street and New Sherborn Road in Athol, then the Monson Turnpike (Turnpike Road) in Petersham, where the road had an intersection with Route 122. Much of the route south of this intersection lies within the Quabbin Reservoir State Reservation.