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Chad Spann rushed for 80 yards and two touchdowns for the Huskies (2-1).
Northern Illinois, a Mid-American Conference school, entered the game 1-32-1 all time against the Big Ten.
Purdue quarterback Joey Elliott passed for 188 yards and ran for 68 yards and two touchdowns. But the Huskies held Ralph Bolden, the nation's leading rusher after two games, to 64 yards.
Purdue (1-2) looked sluggish one week after taking Oregon to the limit in a 38-36 loss. The Huskies outgained the Boilermakers 454 yards to 335 and kept the ball for 41:40.
Purdue trailed 28-21 in the fourth quarter and expected to get the ball back with about 3:30 left after forcing Northern Illinois into a fourth down, but the Huskies resorted to trickery. Justin Anderson took a direct snap on a fake punt 11 yards for a first down. NIU eventually punted but didn't leave Purdue enough time to mount a threat.
Purdue's Aaron Valentin started the scoring with a weaving, bobbing, 62-yard punt return for a touchdown in the first quarter.
Spann's 1-yard touchdown run tied the score in the second quarter, and Brown's 67-yard touchdown run gave the Huskies a 14-7 lead.
Valentin fumbled a punt that NIU recovered at the Purdue 35, but Spann fumbled it right back to Purdue.
Valentin fumbled again on his next return, and NIU recovered at the Purdue 23. The Huskies took advantage this time when Chandler Harnish completed a 10-yard touchdown pass to Reed Cunningham to make it 21-7 at halftime. Northern Illinois outgained Purdue 247 yards to 74 before the break.
Purdue reached the NIU 28-yard line on its second possession of the third quarter, but the Huskies stuffed Elliott on a fourth-and-1 to stop the threat.
NIU came back with a 13-play, 62-yard drive that ended with Spann's 11-yard touchdown run for a 28-7 lead with 2:43 left in the third quarter.
Elliott, not known for his mobility, turned a broken play into a 58-yard touchdown run to cut Northern Illinois' lead to 28-14 heading into the fourth quarter.
Elliott led the Boilermakers on an 11-play, 80-yard drive, then finished it with a 6-yard touchdown run that cut NIU's lead to 28-21 with 5:42 to play.
