Shaking off two second-half turnovers, the first-round draft pick capped a nine-play, 80-yard drive with a 2-yard touchdown pass to Stevie Johnson with 2 seconds remaining in a 24-23 win over the Carolina Panthers on Sunday.
It was the first victory for the new-look Bills under Manuel and coach Doug Marrone. It came on a day when the Bills honored their 28-member Wall of Fame - a group that includes Hall of Famers Jim Kelly, Thurman Thomas and Marv Levy - during a halftime ceremony.
And it came a week after the Bills squandered a last-second lead in a 23-21 season-opening loss to the New England Patriots.
Manuel showed poise in directing a hurry-up offense by completing 6 of 8 attempts for 51 yards. He also got help on third-and-6 from Carolina's 29, when Panthers linebacker Luke Kuechly was penalized for pass interference with 14 seconds left.
Two plays later, Manuel found Johnson alone in the left corner. Manuel was 29 of 37 for 296 yards and bounced back after throwing an interception and losing a fumble on consecutive possessions. Both turnovers led to field goals by Graham Gano.
Manuel became the fifth NFL rookie since 1960 to engineer a fourth-quarter comeback in his first or second game.
Bills defensive end Mario Williams set a team record with 4 1/2 sacks. Fred Jackson scored on a 4-yard run.
The Panthers (0-2) lost yet another close game. They were coming off a 12-7 defeat to Seattle and dropped to 2-14 in games decided by 7 points or less in two-plus seasons under coach Ron Rivera.
Carolina had to settle for field goals on its three final possessions. The first two came when the Panthers were stopped on third down inside the Bills 10.
Cam Newton went 21 of 38 for 229 yards and two touchdowns, a 13-yarder to Greg Olsen and a 40-yarder to Ted Ginn Jr.
Newton delivered on his goal of opening up the Panthers' passing game after he was limited to a career-low 125 yards last weekend. The trouble was he still had difficulty completing passes to anyone other than Olsen or Steve Smith, who combined for 12 catches for 136 yards.
The Panthers' usually stout defense had an unlikely second-half meltdown. The Bills had four scoring drives on six possessions - and also scored on a 2-point conversion when Manuel hit rookie receiver Robert Woods.
Carolina's secondary was thinned by injuries. Starting cornerback Josh Thomas (concussion) and starting safety Charles Godfrey (right ankle) did not return after both were hurt.
Newton led a 12-play, 39-yard drive that ate up more than 5 1/2 minutes, capped by Gano's 39-yard field goal with 1:38 left.
Manuel was unfazed as the Bills took over at their own 20 with 1:38 remaining and no timeouts. Willing to throw over the middle, he was efficient in twice getting the Bills lined up when his receiver was unable to get out of bounds.
The Bills won despite an ongoing lack of discipline. They were penalized seven times for 55 yards, a week after being flagged 10 times for 75 yards against New England.
Punting on fourth-and-18, Carolina got a fresh set of downs when Bills fullback Frank Summers was flagged for holding before the punt. The Panthers capitalized four plays later, when Newton hit Ginn for a 40-yard touchdown pass to put Carolina ahead 14-6.