Eli Manning's frustrating season went from bad to worse early on after the Bears had won the coin toss and put the Giants into offense.
The 32-year-old threw two interceptions in the first quarter, taking his total to 14 for the season, in his first five passes, although his first error went unpunished.
It was Tim Jennings who ran home a 48-yard touchdown after intercepting a pass to put the home side on the board.
Tom Coughlin's men were level before the end of the first quarter thanks to Brandon Jacobs powering through from three yards, but the Bears retook the lead 42 seconds into the second quarter, with Brandon Marshall profiting from Jay Cutler.
However, Manning picked out Rueben Randle to weave his way across the line as the visitors roared back once more, but Cutler and Marshall combined once again before Robbie Gould kicked a field goal to see the Bears lead at half time.
Gould nailed another kick in the third quarter to stretch the lead to 13 points, But the big move was made by the Giants, with Jacobs once again battering his way into the endzone.
That reduced the deficit to six heading into the fourth quarter and the Giants were now in the ascendancy, but a third interception of the night for Manning with just under two minutes left killed any hope of a comeback.
It is the first time since 1976 that the Giants have gone 0-6, while victory sees Marc Trestman's side go 4-2 and they now top the NFC North division.