The Chiefs started the game well as Alex Smith and his offense were in rhythm early on, but the Giants' defense held them until the start of the second quarter when he finally punched the ball into the end zone, finding tight end Sean McGrath on a five-yard strike.
Smith rallied his team after the strike from the Giants and led them downfield, but they were forced to settle for a field goal as the visitors kept them out of the end zone. Ryan Succop nailed a 51-yard effort through the posts to restore their lead.
Just before the break, New York kicker Josh Brown had the chance to tie the scores with a 44-yarder, but he drilled his effort just wide of the left upright.
After half time, the game became sloppy as both quarterbacks started to make errors. Smith threw an interception right into the hands of Giants cornerback Prince Amukamara when he looked to find Dwayne Bowe.
However, Manning then also threw an interception just two plays later when he was picked off by Chiefs safety Quentin Demps when trying to find Hakeem Nicks. But just plays later Smith's pass was deflected and caught by Antrel Rolle for yet another turnover.
The Giants could not turn the interception into points, though, as their offense continued to struggle.
Andy Reid's side made them pay for this when they punted the ball away as Dexter McCluster returned Steve Weatherford's kick 89 yards for a touchdown to extend his side's lead to 10 points.
The Chiefs piled the agony on for the Giants after another special teams gaffe as they committed a penalty, which allowed the home side to extend their drive and add to the score as Smith found Jamaal Charles in the end zone for a two-yard touchdown.
It was not over there for the Giants as Smith notched his third touchdown pass of the game as he found Dwayne Bowe down the right-hand sideline for a 31-yard strike to seal an emphatic win.