State Route 221 (SR 221) is a state highway in Napa County of the U.S. state of California.

Route 221 is the northernmost part of the Napa-Vallejo Highway. It is a divided four-lane expressway that serves as an alternate to the nearby Route 29 freeway into Napa from the south. It is only signed as a number on a junction sign at the intersection with Route 29. The southern terminus is with Route 29 (which also carries Route 12), where it continues as the Napa-Vallejo Highway, and the northern terminus is an intersection with Route 121. Route 221 also provides direct access to Napa Valley College.

Except where prefixed with a letter, postmiles were measured on the road as it was in 1964, and do not necessarily reflect current mileage. The entire route is in Napa County.