Manning recovered from a miserable start to the game to register an outstanding second-half performance.
Manning's yardage figures were the second best in Giants' history and the seventh best overall in NFL history, and came after a first-half display that saw the quarterback throw three interceptions.
The reigning Super Bowl champions trailed by 14 points at one stage, but Manning came out firing after the break.
Manning threw touchdowns to Hakeem Nicks, Victor Cruz and Martellus Bennett before Andre Brown's two-yard run with 30 seconds remaining secured a thrilling comeback win.
Stephen Gostkowski fluffed a late field goal attempt as the New England Patriots slipped to a 20-18 defeat at the hands of the Arizona Cardinals.
Kevin Kolb threw one touchdown and ran one in to help the Cardinals to victory, but the Pats should have been the team celebrating.
Trailing by two, the Patriots recovered the ball on the Cards' 30-yard line after a fumble with a minute remaining and thought they had won the game when Danny Woodhead ran the ball in only for the officials to call the play back for a holding penalty.
Tom Brady then spiked the ball with six seconds remaining to tee up a 42-yard kick for Gostkowski, but his effort drifted wide as the clock ticked down.
Cam Newton starred for Carolina as the Panthers defeated the New Orleans Saints 35-27.
Newton threw for 253 yards and ran a career-high 71 yards to pace the Panthers to victory and condemn Drew Brees and the Saints to a 0-2 start.
The Philadelphia Eagles won by a one-point margin for the second week in succession as they defeated the Baltimore Ravens 24-23.
A week after edging out the Cleveland Browns 17-16, the Eagles managed another thrilling win that was clinched when quarterback Michael Vick ran in a one-yard touchdown inside the final two minutes.
Number one draft pick Andrew Luck lived up to some of the hype as he led the Indianapolis Colts to a 23-20 win over the Minnesota Vikings.
Luck threw two touchdown passes and marched the Colts down the field to tee up Adam Vinatieri for the game-winning field goal with less than 10 seconds remaining.
Ben Tate scored two touchdowns and Arian Foster ran for 110 yards and a TD to help the Houston Texans to a 27-7 win at the Jacksonville Jaguars, while Andy Dalton threw three touchdown passes as the Cincinnati Bengals won 34-27 against the Cleveland Browns.
Reggie Bush ran for 172 yards and two touchdowns to lift the Miami Dolphins to a 35-13 win over the Oakland Raiders, while C.J. Spiller had 123 yards rushing, 47 yards receiving and two TDs as the Buffalo Bills defeated the Kansas City Chiefs 35-17.
Sam Bradford threw for 310 yards and three touchdowns for the St Louis Rams, who hit back to edge past Washington 31-28.
The Redskins had led 21-6 midway through the second quarter but receiver Danny Amendola and Bradford inspired the Rams' comeback.
Amendola tied an NFL record 12 first-half receptions and narrowed the deficit by catching a touchdown pass before Bradford set up Brandon Gibson and Matt Mulligan with scoring passes in the second half.
Ben Roethlisberger impressed for Pittsburgh Steelers as they put on a strong second-half performance to ease past the New York Jets 27-10.
Roethlisberger passed for 275 yards and two touchdowns, hitting Heath Miller to give the Steelers the lead late on in the second quarter before extending his side's advantage by teeing up Mike Wallace for a 37-yard score.
Isaac Redman added a late two-yard touchdown for Pittsburgh, who only had a slim 13-10 lead at the end of the first half.
San Diego recorded their ninth successive victory over the Tennessee Titans, with tight end Dante Rosario taking three touchdown passes for the first time in his professional career to see the Chargers to a 38-10 victory.
Marshawn Lynch ran for 122 yards and a touchdown in the final quarter as the Seattle Seahawks breezed past the Dallas Cowboys 27-7.
Finally, Vernon Davis caught two touchdown passes from Alex Smith as the San Francisco 49ers beat the Detroit Lions 27-19.
Smith threw for 226 yards, which included passes of 21 and 23 yards for Davis to touch down, as the 49ers followed up last week's season-opening victory at Green Bay with another impressive win.