Manning capped a decisive drive eerily similar to the one in the 2008 Super Bowl, throwing a 1-yard touchdown pass to Jake Ballard with 15 seconds left and giving the Giants a 24-20 win on Sunday.
"I knew we would win," Giants running back Brandon Jacobs said. "It definitely took me back to the Super Bowl."
In that 17-14 victory, Manning threw a 13-yard scoring pass to Plaxico Burress with 35 seconds to go. Four plays earlier, David Tyree trapped Manning's third-down pass over the middle on top of his helmet for a 32-yard gain.
On Sunday, the teams met in a meaningful game for the first time since then. And Manning threw another completion over the middle to an unheralded receiver on third down, connecting with a leaping Ballard for a 28-yard gain. Five plays later, they hooked up for the winning pass.
"If it was thrown anywhere else, I wouldn't have caught it," Ballard said. "You dream about making catches like that."
And Ballard's number? The same as Tyree's, 85.
Manning, of course, threw all those passes, outplaying Tom Brady, who is known for his fourth-quarter comebacks.
"I'd rather be down by three with a minute-thirty (left) than up by four with a minute-thirty with Tom Brady, with their offense on the field," Manning said. "You like those situations where you have an opportunity to go win the game."
"We've got half the season to go," Brady said. "We'll see what our team's made of this week."
The loss ended several impressive streaks: wins in an NFL-record 31 regular-season starts at home for Brady and in 20 regular-season home games for the Patriots.
Brady did throw a touchdown pass for the 24th straight regular-season home game. But the Patriots lost consecutive games for just the third time since the start of the 2003 season.
The Giants won for the sixth time in seven games.
"We got a little carried away," defensive end Justin Tuck said when asked about players lifting coach Tom Coughlin on their shoulders in the locker room. "Considering how good that team is and what they've done here in the last 20 games, it was a big win, and to win it in the fashion that we won it, it brings back memories."
For a while, it looked like the Patriots would win with a comeback when Brady threw a 14-yard pass to Rob Gronkowski, making it 20-17 with 1:36 to go.
But the Giants had enough time. And they had Manning.
They were helped by a 20-yard pass interference penalty against Sergio Brown that put the ball at the 1 with 30 seconds left.
"I was looking at the ball the whole time," Brown said. "I was surprised. They come and tell us as long as we're looking at the ball we can play the ball."
Three plays later, Manning found Ballard in the back left corner of the end zone.
"I knew I'd be hit hard," Ballard said. "I concentrated as hard as I could."
He was guarded by Kyle Arrington.
"We're going to be hard on ourselves," Arrington said. "We don't take losing well."
After a scoreless first half, the Patriots took their first lead, 13-10, on Stephen Gostkowski's 45-yard field goal with 7:08 to go in the game. Manning then led the Giants on an 85-yard march to a 10-yard touchdown pass to Mario Manningham with 3:03 remaining.
The Giants won despite injuries that kept their top rusher, Ahmad Bradshaw, and leading receiver, Hakeem Nicks, from making the trip. But New York's defense pressured Brady much of the game, coming up with two sacks and two interceptions.
Manning completed 20 of 39 passes for 250 yards with two touchdowns and one interception. Brady was 28 for 49 for 342 yards and two touchdowns.
Both quarterbacks struggled throughout the first half.
The offense was so bad that fans booed when Brady threw an incompletion with 8:30 left in the third quarter. They cheered on the next play when Aaron Ross fumbled Zoltan Mesko's punt and Rob Ninkovich recovered.
But the Patriots managed just a 32-yard field goal by Gostkowski that cut the lead to 10-3.
Manning moved the Giants from the Patriots 40 to a third-and-goal at the 5, then threw an interception to Arrington in the end zone. Seven plays later, Brady hit Aaron Hernandez for a 5-yard touchdown, tying the game at 10 just 32 seconds into the fourth quarter.
The Giants had much better field position in the first half, starting at their 23, 22, 36, 28, 25 and 49. But all those series ended with punts.
The Patriots began at their 5, 6, 17, 20, 11 and 9. They punted four times and lost one interception before wasting their best scoring opportunity when Gostkowski pulled his 27-yard field goal attempt to the left with 3 seconds remaining. On that drive, the Patriots had five first downs, matching their total to that point.
The Giants have forced at least one turnover in 21 straight regular-season games. ... Giants DE Jason Pierre-Paul had a sack for the fifth straight game. ... The Giants have 14 players remaining from the 2008 Super Bowl team, the Patriots have seven.
NFL fines Browns' Ronnie Harrison for shoving Chiefs assistant Greg Lewis
Cleveland Browns safety Ronnie Harrison Jr. was fined $12,128 by the NFL for shoving Kansas City Chiefs running backs coach Greg Lewis during their game last Sunday.
New Orleans Saints lose two more assistants for game vs. Carolina Panthers amid COVID-19 protocols
The Saints announced Saturday defensive line coach Ryan Nielsen and pass rush specialist Brian Young will not be with the team for its second game of the year due to NFL COVID-19 protocols, joining six others from New Orleans coach Sean Payton's staff.
Philadelphia Eagles sign DE Josh Sweat to three-year extension
The Eagles have signed defensive end Josh Sweat to a three-year extension, the team announced. The deal could be worth up to $43 million and includes $26.9 million guaranteed, sources told ESPN's Adam Schefter.
Stephen A. blasts Joe Judge for Giants' loss at Washington
Stephen A. Smith and Tim Tebow debate who is most at fault for the Giants' last-second loss to the Washington Football Team.
New England Patriots-New York Jets rivalry goes to Gen Z at QB: Mac Jones, Zach Wilson
For the first time in the 62-year history of the series, these teams will start rookie quarterbacks against each other. Learn more about them for Week 2.
Former rivals, future stars: How Titans' A.J. Brown and Seahawks' DK Metcalf got here together
From high school competitors to becoming like brothers, Brown and Metcalf have achieved success together and keep pushing each other forward.