At one point, the status of New England wide receiver Danny Amendola was unclear.
Wes Welker's replacement aggravated a groin injury that limited him in practice during the week late in the second quarter.
Amendola returned, however, to play a key role in the Patriots' season-opening 23-21 come-from-behind win over the Buffalo Bills at Ralph Wilson Stadium.
Trailing by a point, the New England defense forced a three-and-out against the aggressive play-calling of the Bills' Doug Marrone, who made his NFL debut as a head coach. Instead of relying on the running game to eat up more of the clock, Buffalo opted to pass and rookie EJ Manuel, the first quarterback chosen in April's draft at No. 16, picked up only four yards on 3rd-and-10.
"It wasn't a situation we felt we needed to milk the clock," Marrone said. "We felt that we still needed to score to win the game."
The Patriots got the ball back with 4:31 to play in the fourth quarter, and quarterback Tom Brady twice hooked up with Amendola to convert third downs, the latter a 10-yard gain on 3rd-and-8 from the Buffalo 39.
Shane Vereen followed with a 15-yard run around left tackle on the next play, setting up Stephen Gostkowski's game-winning 35-yard field goal with five seconds left.
"I was proud of our team today. They made the plays they needed to make at the end to win," said Patriots head coach Bill Belichick.
Brady finished with 288 yards, two touchdown passes to Julian Edelman and one interception while completing 29-of-52 throws.
Vereen totaled 101 yards on 14 carries and added 58 yards on seven receptions for the Patriots (1-0), who have won 10 consecutive season openers, the longest current streak in the NFL. Amendola made 10 grabs for 104 yards.
New England was coming off a tumultuous offseason during which Brady lost several offensive weapons, including tight end Aaron Hernandez, who was released following his stunning June arrest on a murder charge. Welker bolted to Denver as a free agent, and tight end Rob Gronkowski missed the Week 1 contest as he continues to recover from forearm and back surgeries.
Manuel connected on 18-of-27 passes for 150 yards and two touchdowns, the second putting the Bills (0-1) up 21-17 with 11:03 remaining in the third quarter.
Buffalo came out running the ball to open the second half, with the combination of C.J. Spiller and Fred Jackson advancing the Bills close to midfield before Manuel scrambled 19 yards to the New England 36. The impressive drive resulted in Manuel hitting Stevie Johnson for an 18-yard scoring strike over defensive backs Kyle Arrington and Devin McCourty.
The Patriots marched to the Buffalo 1 on the ensuing possession, but Brady fumbled the exchange and the Bills recovered.
New England reached the red zone again in the fourth quarter, and Gostkowski drilled a 33-yard field goal with 10:48 to go.
New England and Buffalo each committed two turnovers in a first half that ended with the Patriots up 17-14.
Arrington forced a pair of fumbles, including one by Spiller on the Bills' second play of the game. Defensive lineman Tommy Kelly recovered for New England at the Buffalo 16-yard line, and Brady quickly hooked up with Edelman for a 9-yard touchdown.
The next New England drive ended with Gostkowski making a 48-yard field goal, and the Patriots were looking to add to their lead in the second quarter, marching into Buffalo territory.
However, running back Stevan Ridley went down to the ground untouched and lost the football. Free safety Da'Norris Searcy scooped up the fumble, dodged a tackle attempt by Brady and raced 74 yards to the end zone.
The Patriots were able to regain their 10-point lead just past the two-minute warning when a second Brady-to-Edelman connection followed another turnover created by Arrington.
New England's defense then forced a three-and-out, giving the offense an opportunity for more points. On second down, though, Brady had his pass to Zach Sudfeld go off the hands of the rookie tight end and into the chest of cornerback Justin Rogers for an interception at the New England 37.
Manuel threw consecutive completions, the second to Robert Woods for an 18- yard touchdown with 34 seconds remaining.
Brady has now thrown a TD pass in 49 straight games, five shy of Drew Brees' NFL record ... Brady became the ninth player in NFL history to reach 45,000 career passing yards ... New England has won 11 straight games against AFC East opponents ... The Patriots have forced a turnover in 28 straight games ... Ridley became a spectator following his fumble ... The Patriots have won 19 of the past 20 games against Buffalo.