The defending Super Bowl champion Giants (5-1) were pounded 35-14 by the Browns Monday but led all the way against San Francisco.
Jacobs had touchdown runs of 26 and 2 yards against the 49ers (2-5), who have lost four straight games.
Eli Manning passed for 161 yards and a touchdown and Michael Johnson picked off two passes by the 49ers' J.T. O'Sullivan, who was 16-of-28 passing for 256 yards and touchdown.
Nate Clements returned a blocked field goal attempt 74 yards for a touchdown and Josh Morgan caught five passes for 86 yards and a score for the 49ers.