Chandler Whitmer, who completed passes to eight different receivers, 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.
McCombs, UConn's 166-pound tailback was the Huskies' workhorse, carrying the ball 29 times for 97 yards. His 2-yard fourth-down touchdown run gave the Huskies a 24-7 lead with just over 5 minutes left in the third quarter.
But Buffalo went into its bag of tricks to pull within 24-14. Zordich completed a 4-yard pass to Alex Neutz in the right flat, who then pitched the ball to running back Brandon Murie. He raced down the right sideline, breaking a Byron Jones' tackle on the way to a 50-yard touchdown.
The Bulls got within a touchdown on a 44-yard field goal by Patrick Clarke with 2:23 left after a 43 yard pass from Zordich to Neutz.
UConn receiver Geremy Davis recovered the onside kick, but UConn punted it away three plays later giving Buffalo one more chance to tie.
The Bulls took the ball at their own 20 and managed one first down. But Zordich was stuffed by linebacker Yawin Smallwood after a 2-yard gain on a fourth-and-4 from the 39, and the Huskies ran out the clock.
Connecticut had big plays on back-to-back drives in the first half to take a 17-7 lead.
Tight end Ryan Griffin's 36-yard catch and run over the middle on the first play of the second quarter capped a 10-play, 92-yard drive that gave the Huskies a 10-7 lead.
The Huskies then went 75 yards in five plays the next time they had the ball. Hyppolite, who had just four carries coming into the game, took a pitchout on his fifth and went 50 yards off the right side for the Huskies second touchdown.
But Buffalo responded with a 10 play, 75-yard drive that included a 30-yard screen pass to Devin Campbell on a fourth down that set up Murie's 4-yard touchdown run.
The Bulls' special teams then stepped up, executing a successful onside kick, before the offense stalled.
Buffalo clearly missed Oliver, who had rushed for 426 yards in just over two games this season before going down with what the team has only described as a leg injury in the first half of the Bulls' Sept. 19 loss to Kent State. Oliver rushed for 1,395 yards and 13 touchdowns last season for the Bulls.
Without him, Zordich was the Bulls most effective ball carrier. He had 66 yards rushing in the first half.
Running backs Murie (55 yards) and Campbell (25), combined for 80 yards rushing in Oliver's place. They had a combined 18 carries coming into the game.
UConn came in ranked fifth in the nation against the rush, allowing just 51 yards per game, but gave up 141 to the Bulls.
Buffalo came into the game giving up 34 points a game.
The Huskies improved to 12-4 at Rentschler Field over the last three seasons.
Nike Men's UConn Huskies Blue Football Icon Legend T-ShirtShop
Florida State coach Jimbo Fisher hopes quarterback Sean Maguire is ready to go full speed by the middle of June.
Graduate transfer quarterback Davis Webb has officially joined California, giving the Golden Bears an experienced option to replace No. 1 overall NFL draft pick Jared Goff.
First-year football coach Dino Babers, hired by former Syracuse AD Mark Coyle, is on the committee that will search for Coyle's replacement.
Hugh Freeze has some major holes to fill on offense with the departures of Laremy Tunsil and Laquon Treadwell, but there is Chady Kelly and good depth.
After transferring in from Montana State, Dakota Prukop has a checklist he's working from as he prepares to compete for the Oregon job.
The destination for Week 6 of the Big 12 Ultimate Road Trip is unanimous, as all three conference reporters would head to the Red River Rivalry.