Along the way it intersects several major highways including Interstate 90 (I-90) in Ludlow and US 202 and Route 181 in Belchertown.

It heads north, intersecting with Route 141 before crossing the Chicopee River into Ludlow.

It continues through town, passing south of the Springfield Reservoir before heading northward into Belchertown.

Much of the route south of this intersection lies within the Quabbin Reservoir State Reservation.

[2] Into the 1970s, MA-21 started in Forest Park with an intersection with U.S. Route 5 near the South End Bridge.