Manning did the same four years ago when New York ruined New England's perfect season.
Manning not only has stamped himself as the elite quarterback he claimed to be when the season began - in the same class as Brady - he's beaten the Patriots in two thrilling Super Bowls.
The latest one was in older brother Peyton's house at Lucas Oil Stadium in Indianapolis, Ind.
The Giants (13-7), who stood 7-7 in mid-December, now own their fourth championship title, and Manning owns two Super Bowl MVP awards, the same number as Brady.
It was a classic can-you-top-this showdown, and Manning won. He finished 30-for-40 for 296 yards and one touchdown, while Brady was 27 for 41 for 276 yards, with two TDs and one interception.
"It's been a wild game, a wild season," Manning said. "This isn't about one person. It's about one team, a team coming together."
Manning led six comeback victories during the season and set an NFL record with 15 fourth-quarter touchdown passes. He showed that brilliance in the clutch on the winning drive. He completed five passes, including a sensational 38-yard sideline catch by Mario Manningham to open the drive.
Brady headed off with his head bowed, holding his helmet, while around him was the wild celebration by the Giants, NFL champions for the eighth - and perhaps most unlikely - time.
Brady and coach Bill Belichick were in their fifth Super Bowl together - that's the most by a head coach and starting quarterback. They've had only lost five playoff games in their collective careers
Some of the fastest football action happened 1,600 miles away in Las Vegas.
As much as $93 million was expected to be wagered on the Super Bowl, making it the single biggest sporting event of the year for betters.
And it wasn't just about who would win or lose.
There were side bets on whether Chad Ochocinco would score a touchdown and if the first player to score would have an odd or even numbered jersey.
People even wagered on if the Patriots would score more points than Lebron James did for the Miami Heat in Sunday's
The Associated Press contributed to this report.