Kevonte Martin Manley had seven catches and a TD for the Hawkeyes (2-1). Iowa ran the ball 60 times for 218 yards and snapped a two-game losing streak against the Cyclones.
Quenton Bundrage rallied the Cyclones with two touchdown receptions in the final 4:27. But Iowa recovered an onside kick and snuffed out a last-gasp try by Iowa State.
Bundrage had a career-high 146 yards receiving and all three TD grabs for Iowa State, which is 0-2 for the first time since 2007.
Iowa appeared to have the game in hand when it went up 27-7 with 7:05 left.
The Hawkeyes inexplicably let the Cyclones back in it - despite a spectacular one-handed interception by Iowa's B.J. Lowery.
Richardson found Bundrage for TD passes of 26 and 17 yards, pulling Iowa State within 27-21 with 2:26 to go as streams of Cyclones fans headed for the parking lot.
The Hawkeyes then recovered an onside kick, but they couldn't get a first down. Iowa was forced to punt it back to the Cyclones, whose lateral-filled final play went nowhere.
Sam Richardson, clearly still hampered by the ankle he sprained in the opener two weeks ago, was 22 of 39 passing for 260 yards and two picks.
Despite a terrible start on offense, Iowa State got back in the game with one throw.
The Hawkeyes answered by beating the Cyclones on a similar scoring play - and then ran right through the heart of Iowa State's defense.
Bundrage caught a ball near the sidelines and got past Lowery and the rest of Iowa's defense for a 67-yard touchdown, making it 13-7 Iowa with 5:28 left in the third quarter.
But Rudock found Jacob Hillyer near Iowa State's 15-yard line, and he beat a pair of Cyclones defenders for a 26-yard TD reception and a 20-7 lead just before the start of the fourth quarter. The Hawkeyes then ran 14 times in 15 plays on the weary Cyclones, a drive that ended on a 1-yard TD plunge by Rudock.
Weisman had a touchdown overturned by replay in the fourth quarter, but was by far the focal point of Iowa's offense, even though he failed to find the end zone.
Weisman has rushed for at least 100 yards in Iowa's first three games. The last Hawkeye to do that was Shonn Greene five years ago, when he won the Doak Walker Award as the nation's top running back.
Establishing the run figured to be crucial in this matchup. Iowa and Iowa State both have sophomore quarterbacks - with Rudock in his first career start and Richardson coming off a sprained ankle - and much more quality depth at running back than at wide receiver.
The Hawkeyes got their ground attack going early, and they never let the Cyclones do the same.
The Hawkeyes went on a 15-play drive late in the first half that took more than 7 minutes and also featured just one pass. It only resulted in a 27-yard field goal by Mike Meyer, but it sent a clear message that Iowa could do what it wanted even when the Cyclones knew what was coming.
Iowa State rushed for just 59 yards on 24 carries.