Manning became just the 13th player in NFL history to pass the magical 500-yard milestone when he recovered from a sloppy start to steer the Giants to a 41-34 win over the Tampa Bay Buccaneers.
Manning threw three interceptions in the second quarter that all led to touchdowns but, just as he did last season when the Giants defied the odds to win the Super Bowl, he found his targets when it mattered.
"It's a big win, big win, especially after a first half playing poorly and last week not playing well. The second half was good," Manning said.
"Some big time plays, stepping up when we needed it. That was fun."
The New England Patriots, last season's beaten Super Bowl finalists, were not so lucky, suffering a shock 20-18 loss at home to the Arizona Cardinals.
The Cardinals led most of the game but the Pats, led by Tom Brady who threw for 316 yards, had the chance to win it at the death but Stephen Gostkowski missed a 42-yard field goal attempt.
"I have to do a lot better job of coming through for the team," said a dejected Gostkowski. "It came down to me and I didn't pull through. It stinks."
Alex Smith proved once again he can handle the big moment, leading San Francisco to a game-clinching drive that finished off the Detroit Lions 27-19 on Sunday and kept the 49ers' perfect start intact.
Smith was flawless in throwing for 226 yards and two scores, and engineered a 13-play 79-yard march downfield that gave the home team a 15-point lead with just 3:04 remaining.
Detroit (1-1) answered with a late touchdown, but it was too little, too late.
"We were able to hold on and it was a heck of a team win," 49ers defensive tackle Justin Smith told reporters. "We have a lot of players and a one-game mentality. We just keep chopping wood and we were able to get another one."
The New Orleans Saints, operating under an interim coach in the wake of the 'pay-for-pain' scandal, slumped to their second loss of the season when they were beaten 35-27 by the Carolina Panthers.
Cam Newton, in just his second season in the NFL, threw for a touchdown and was one of three Carolina players to rush for a score against a leaky New Orleans defence.
Philadelphia quarterback Michael Vick scored a touchdown with less than two minutes left on the clock to guide the Eagles to a 24-23 comeback win over the Baltimore Ravens.
The Eagles trailed for most of the game but Vick sealed the win when he orchestrated a final quarter 80-yard, 10-play drive that finished with him scoring the game winner from a yard out.
Rookie quarterback Andrew Luck, last season's number one draft pick, registered his first NFL win when the Indianapolis Colts beat the Minnesota Vikings 23-20.
Luck threw two touchdown passes then found wide receivers Donnie Avery and Reggie Wayne in the final 30 seconds to set up Colts' kicker Adam Vinatieri for a game winning 53-yard field goal.
Another rookie quarterback, Robert Griffin III, tasted his first defeat when the Washington Redskins lost 31-28 to the St Louis Rams.
The Pittsburgh Steelers won their first game of the season, beating the New York Jets 27-10 while the Houston Texans had no problems overcoming the Jacksonville Jaguars 27-7 in Florida.
Dante Rosario scored three touchdowns for San Diego as the Chargers romped to a 38-10 victory over Tennessee to join the Eagles, Cardinals and Texans as the only teams to start the season 2-0 with two games left in the round.
Miami, Cincinnati, Seattle and Buffalo all chalked up their first wins of the season with the Dolphins defeating the Oakland Raiders 35-13, the Bengals beating the Cleveland Browns 34-27 the Seahawks overpowering Dallas 27-7. The Bills downed Kansas City 35-17.
Just six of the 32 teams in the NFL are yet to win after two weeks: New Orleans, Cleveland, Jacksonville, Tennessee, Kansas and Oakland.