UConn turned the ball over five times and remains winless through four games. The Huskies struggled to find any offense behind quarterback Chandler Whitmer, increasing the pressure on third-year Connecticut head coach Paul Pasqualoni.
Buffalo (2-2) scored through the air, on the ground and on defense in building a 28-12 halftime lead. They blocked a field goal and scored 17 points off Connecticut turnovers.
Bulls quarterback Joe Licata passed for a career-high three touchdowns, connecting with different receivers on each score. Licata found tight end Mason Schreck for a 5-yard touchdown in the first quarter, later adding a 22-yard touchdown to Alex Neutz and a 36-yard score to Fred Lee.
The Bulls were aided by the return of starting running back Branden Oliver, who had 110 total yards including 90 yards rushing and a touchdown.
Whitmer turned the ball over four times, including a second-quarter interception that Najja Johnson returned 33 yards for a Bulls touchdown.
Patrick Clarke hit field goals of 49 and 50 yards for Buffalo.
Receiver Geremy Davis was a bright spot for the Huskies, with five catches for 102 yards.
The Huskies continue to have trouble on the ground. Entering the game 121st in rushing offense, they finished the game with 27 yards rushing on 39 attempts.
The win was Buffalo's first against a BCS school since Sept. 7, 2002, when they beat Rutgers.
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Running back Devontae Booker had 124 combined yards and a touchdown, and Utah spoiled Jim Harbaugh's Michigan coaching debut, beating the Wolverines 24-17 on Thursday night.
Arizona star linebacker Scooby Wright will have an MRI after injuring his left knee in the first quarter of the Wildcats' season-opening 42-32 win over UTSA on Thursday night.
Trevone Boykin threw for 246 yards and a touchdown and ran for 92 yards and another score to help No. 2 TCU outlast Minnesota 23-17 on Thursday night.
All-American defensive end Shawn Oakman and safety Orion Stewart have been suspended for Baylor's season opener Friday against SMU for a violation of team rules, a school spokesman told ESPN.com.
Ohio State quarterback Cardale Jones is "doing fine" after he was released from the hospital Wednesday night after being treated for symptoms related to a migraine headache.
East Carolina receiver Trevon Brown will miss three games after being placed on probation for a violation of the school's student code of conduct.