Chandler Whitmer threw for 227 yards and another score as UConn (3-2) opened up a 24-7 lead in the third quarter and held on to win.
Buffalo (1-3), which was playing without injured running back Branden Oliver, had the ball with a chance to tie late in the game, but failed to convert on fourth down at its own 39 yard line.
Quarterback Alex Zordich threw for 220 yards and ran for 76 to lead the Bulls.
UConn improved to 2-1 this season against the Mid-American conference. The Huskies beat Massachusetts in their season opener, but lost last week at Western Michigan.