Bradshaw carried the ball 27 times, becoming the first runner to log a 100-yard-plus performance against the 49ers in almost two years as the Giants rolled to a victory in a rematch of last year's NFC championship game.
Eli Manning completed 15-of-28 passes for 193 yards, hooking up with Victor Cruz on a scoring strike for New York (4-2).
Hakeem Nicks helped out with three grabs for 44 yards in the victory.
Alex Smith finished with 200 passing yards on 19-of-30 efficiency, but was done in by the three Giants pickoffs.
San Francisco (4-2) managed just 314 yards of total offense.