Manning completed 15 of 30 passes for 203 yards and two scores in the 23-17 setback at Lincoln Financial Field in Philadelphia. Eagles quarterback Carson Wentz completed 33 of 50 passes for 325 yards and two scores.
The win gives the Eagles a 6-7 record, matching the Dallas Cowboys atop the NFC East.
"It's huge for us," Wentz told reporters. "Obviously we realized it was a sloppy game for a while, but the way guys just hung tough and stayed together more importantly. We dealt with some injuries and some other guys stepping up and making plays and that was huge."
Manning made his first start since being benched for rookie Daniel Jones in Week 2.
"I missed my first throw, which should have been an easy throw," Manning said. "After that, I think I got things going a little bit and hit a couple of completions. It was good to get a two-minute drive before the half and get into a rhythm. Unfortunately, we just couldn't find it in the second half."
The Eagles and Giants played a scoreless first quarter before Manning orchestrated a seven-play, 62-yard touchdown drive to start the second quarter. He ended the drive by throwing a 35-yard touchdown pass to Darius Slayton.
The Eagles got on the scoreboard on the next drive, with Jake Elliott making a 34-yard field goal. Aldrick Rosas answered with a 34-yard field goal on the Giants' next drive, making the score 10-3.
Manning threw his second touchdown of the first half when he found Slayton again with a 55-yard throw just before halftime.
"Everybody kind of understood what was going on and it was just a matter of pride," Eagles head coach Doug Pederson said. "We just had to kind of figure it out, and defense, again, did a great job in the second half. Really kind of shutting everything down for them and giving the offense opportunities.
"Again, we struggled offensively to start the third quarter, but then kind of got into a little bit of a hurry-up-tempo and got into a rhythm and scored those three scores."
The Eagles began their comeback at the end of the third quarter, using a 10-play, 58-yard drive to cut the Giants' lead to seven points. Boston Scott ended the drive with a two-yard touchdown run.
Wentz connected with star tight end Zach Ertz for a two-yard touchdown with 1:56 remaining to tie the score at 17-17, forcing overtime.
The Eagles used an eight-play, 75-yard drive to win the game in the bonus period. Wentz threw a two-yard touchdown pass to Ertz to win the game.
Ertz had nine catches for 91 yards in addition to his two scores. Scott had 128 yards from scrimmage and a score for the Eagles. Slayton had five catches for 154 yards and two touchdowns for the Giants. Saquon Barkley had 17 carries for 66 yards in the loss. Giants defender Oshane Ximines had two sacks. Vinny Curry also had two sacks for the Eagles.