O'Brien, who went 26-for-37 for 285 yards, hit Glen Fox with a 63-yard touchdown pass and Colin Cochart with a 1-yarder. Fox caught five passes for 99 yards for the Jackrabbits (6-1, 5-0 Missouri Valley).
Peter Reifenrath kicked two short field goals, and Kyle Harris added a 49-yarder.
Quarterback Pat Grace led Northern Iowa (5-3, 3-2) by rushing for touchdowns of 2 and 3 yards. He also passed 38 times, completing 21 for 215 yards. Carlos Anderson rushed 13 times for 79 yards.
The victory created a two-way tie atop the conference with Southern Illinois, which visits South Dakota State on Nov. 7.