The Super Bowl champions sent an ominous warning to their rivals, while Robert Griffin III showed no after effects of his concussion as he helped Washington to a 38-26 win over the Minnesota Vikings.
NFL: Nightmare for Alex Smith as Giants hammer San Francisco
The New York Giants crushed the San Francisco 49ers in an ominous sign of their intentions to defend their Super Bowl title.
The Giants (4-2) made light work of the 49ers (4-2), the team that beat in last year's NFC Conference final, to win 26-3,
San Francisco quarterback Alex Smith endured a torrid time, as the Giants sacked him six times and made three interceptions while New York signal-caller Eli Manning threw for 193 yards and a touchdown, to Victor Cruz.
"Coming in to this game, we knew it was a great challenge to see where we stand," Manning said afterwards.
"That's what we did at the end of last season ... we're getting back into that rhythm of playing smart."
Robert Griffin III ran for 138 yards and two touchdowns, including a 76-yard scamper with 2:43 to play, and the Washington Redskins snapped an eight-game home losing streak Sunday with a 38-26 win over the Minnesota Vikings.
One week after he left the game early with his first NFL concussion, Griffin also completed 17 of 22 passes for 182 yards with one touchdown and one interception.
"I took off running and got to the sideline, thought about running out of bounds - because everyone's been telling me that lately," he said afterwards.
"And I felt like I had the guy outflanked, and then I just took off running. And the rest is history."
Minnesota held an early 9-0 lead but paid the price for getting field goals instead of touchdowns in the red zone.
A 45-yard overtime field goal by Jason Hanson gave the Detroit Lions a 26-23 win over the Philadelphia Eagles.
A fourth quarter rally led by quarterback Matt Stafford saw the Lions register 17 points to extend the game.
The Lions sacked Michael Vick twice on the opening two plays of the extra quarter forcing a punt, and the home side took advantage to claim their second win of the season.
Matt Bryant was the hero for the Atlanta Falcons as his last-gasp 55-yard field goal maintained their unbeaten record at the expense of the Oakland Raiders at the Georgia Dome.
The NFC leaders were pushed all the way by the Raiders, who intercepted Matt Ryan three times, but it was not enough as the Falcons won 23-20 and moved to 6-0 to extend their best start in franchise history.
Atlanta pulled ahead when Asante Samuel returned an interception 79 yards for a touchdown with just over two minutes left, but veteran Carson Palmer led his side up the field as Darren McFadden levelled the scores with 40 seconds left.
That was enough for Ryan to move the Falcons to field goal range and Bryant did the rest.
Running back Shonn Greene ran for a career-high 161 yards and three touchdowns as the New York Jets registered a comprehensive 35-9 win over the Indianapolis Colts at MetLife Stadium.
Rex Ryan's side dominated from start to finish, with his defence shutting down rookie superstar Andrew Luck to snap their two-game losing streak and move to 3-3.
Under-pressure quarterback Mark Sanchez had a solid game throwing two touchdowns as the Jets put in their most dominant performance since their opening day win over divisional rivals Buffalo.
"This is a really good win for us, we certainly needed one," Jets head coach Rex Ryan told reporters. "You can't afford to lose three games in a row at home. We're a tough team and can overcome a lot but we really needed this one."
Cleveland ended an 11-game losing streak with a 34-24 win over the Cincinnati Bengals thanks to two touchdown passes by rookie Brandon Weeden.
It was the Browns' first win since last November as, after the visitors controlled the first half, Cleveland fought back scoring 27 second-half points to take the win.
Quarterback Josh Freeman threw 328 yards and picked up three touchdowns to help the Tampa Bay Buccaneers to a 38-10 win over Kansas City Chiefs.
The Chiefs were without regular starting quarterback Matt Cassel with deputy Brady Quinn intercepted twice, while their running game struggled to get going with back Jamaal Charles rushing for just 40 yards in 12 carries.
Rookie quarterback Ryan Tannehill threw two touchdown passes as the Miami Dolphins picked up their third win of the season with a 17-14 result against the St Louis Rams.
Three points down with seconds left, the visitors put together a late surge leaving Greg Zuerlein a 66-yard field goal to level the game up, but the first year man missed left - one of three field goal failures on the day.
"We know how football is played," Dolphins receiver Davone Bess said.
"It's not about statistics; it's about winning. Pretty, ugly, it doesn't matter. It's just about winning."
Elsewhere, Jacoby Jones equalled an NFL record with a 108-yard kickoff return as the Baltimore Ravens squeezed past Dallas Cowboys 31-29.
Dallas made a record of their own, running 227 yards - their most against the Ravens, but it was not enough as Ray Rice scored two touchdowns as Baltimore moved to 5-1.
A Seattle Seahawks comeback in the final seven minutes allowed them to stun the New England Patriots 24-23.
The matchup between the Patriots' No. 1 ranked offence and Seattle's No. 1 defence instead turned in to a starring performance for Russell Wilson - and a shocking rally.
Wilson hit Braylon Edwards on fourth down for a 10-yard TD to get the Seahawks' within 23-17. After a pair of holds by Seattle's defence, Wilson found Rice open on a double move. Steven Hauschka's extra point gave Seattle the lead.
Tom Brady and the Patriots (3-3) were then stopped on fourth down at their 28 when Wes Welker came up 2 yards short, and the Seahawks (4-2) were able to celebrate the unlikely comeback.
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