For the seventh straight time this season, the New York Giants found themselves in a game that would be decided in the fourth quarter -- and Manning appeared poised to steal one from the upstart San Francisco 49ers.
But Manning finally ran out of his fourth-quarter magic and the Giants literally let a nailbiter slip right through their fingernails, losing 27-20.
Manning hit Hakeem Nicks on a 32-yard touchdown that cut the deficit to seven with 8½ minutes to pay, but just missed on a game-tying touchdown when his 42-yard throw went through Mario Manningham's outstretched fingertips with 2:50 remaining.
"Mario has really got to reach out there, and the ball just doesn't get caught," Giants coach Tom Coughlin said. "You'd have to explain it to me. Sometimes they catch them, sometimes they don't."
As Jim Harbaugh and his Niners (8-1) celebrated yet another tight win, the Giants (6-3) were left with a strange feeling. They lost a close game for the first time since Oct. 9, when they were shocked by the Seahawks, and had a three-game winning streak snapped in the process.
"I thought we were in perfect control," Coughlin said. "I thought we would get there, score to put it in overtime and win in overtime."
The Giants have lived dangerously this season, and while they certainly made enough plays to have sent this to overtime, they also made just enough plays to lose this game.
There isn't much margin for error for the Giants, and the loss of linebacker Michael Boley to a hamstring injury hurt. Boley, who in many ways has been like glue for the depleted defense, left the game for good near the end of the first half. Rookie linebackers Greg Jones and Spencer Paysinger filled in for Boley.
"We were talking about who on this defense is kind of the one that would hurt the most to lose, and unanimously we talked about Boley," defensive captain Justin Tuck said. "He's that guy that gets everybody set up and lined up. I hope [the hamstring injury] is not as serious as it might have looked. We definitely need him."
The Giants were clinging to a 13-12 lead when Steve Weatherford shanked a punt for just 29 yards, giving the Niners the ball at the 50 near the end of the third quarter.
Four plays later, the Niners took advantage of Boley's absence as an uncovered tight end Vernon Davis caught a short pass over the middle and ran in for a 31-yard touchdown, giving San Francisco a 20-13 lead with 13:22 left.
After that, Manning threw his second interception of the day to Carlos Rogers. Manning, who had not thrown more than one interception in a game since the Seattle loss, was not on the same page with Manningham on the play, and it cost the Giants.
Manning still marched the Giants 80 yards in seven plays for a touchdown pass to Nicks, who had to battle extra defensive attention most of the afternoon.
And when Manning got the ball back with 6:35 left down a touchdown, the Giants were preparing for another improbable comeback.
It certainly felt that way when Manning hit Manningham on the left side for an 18-yard gain on a fourth-and-6 to put the Giants at the Niners' 47 with 3:25 remaining.
But then Manning just missed Manningham on what looked like a sure touchdown.
Manning still got the Giants down to the Niners' 10 with a second-and-2 and 1:24 to go. But Manning missed Mannigham again and then D.J. Ware couldn't gain anything on a draw.
So the Giants were faced with converting their third fourth down of the drive with 37 seconds to go.
"We ran something we do very well," Coughlin explained. "Most of these people can do that [play] in their sleep."
Unfortunately for the Giants, Smith didn't fall asleep on the play.
"[Cruz] did a good job of beating his guy and [Jake] Ballard was being held, it looked like, by Patrick Willis," Manning said. "It was a little tight and they overlapped each other and I still tried to fit it in."
The ball was batted down and now the Giants' lead in the NFC East is down to one over Dallas (5-4). The Eagles (3-6) come to MetLife Stadium playing for their season while trying to ruin the Giants' division title chances.
Still, the Giants left San Francisco feeling confident, knowing they could have found a way to win a tough road game had they just played cleaner and made plays like Manningham's finger-tip miss. And they know they still control their own playoff destiny with seven games left, two of them against the Cowboys.
"We are going to see the San Francisco 49ers again," running back Brandon Jacobs said of a potential playoff rematch. "We will see them again."