On September 13, Iowa opened its 1980 season with a 16–7 victory over Indiana. Jeff Brown rushed for 176 yards and caught five passes in his first start as Iowa's tailback.
On September 27, Iowa played Iowa State in the fourth modern edition of the Iowa–Iowa State football rivalry, a game dubbed "Sic Em IV". Iowa lost by a 10–7 score before a crowd of 60,145 at Kinnick Stadium in Iowa City. Iowa quarterback Phil Suess threw a 20-yard touchdown pass in the second quarter, but he was unavailable to play in the second half after sustaining a sprained shoulder on his throwing arm. With less than a minute to go, Iowa drove to Iowa State's nine-yard line, but opted to go for the win rather than kick a game-tying field goal.
On October 4, Iowa lost to Arizona, 5–3, before a crowd of 59,950 at Kinnick Stadium in Iowa City. After fans booed the Hawkeyes during the game, Iowa coach Hayden Fry noted that "Iowa fans have more experience at booing than anybody else in the country." Iowa's only points came on a Reggie Roby field goal in the fourth quarter. Roby then missed a 48-yard attempt with 2:28 remaining in the game. Iowa also gave up two points on a safety when Arizona blocked a punt out of the end zone.
Illinois
On October 11, Illinois defeated Iowa, 20–14, before a crowd of 59,780 at Kinnick Stadium. Illinois led, 20-0, early in the third quarter when Illinois cornerback Rick George returned a fumble 13 yards for a touchdown on the third play of the second half. Iowa then mounted a comeback that fell short. Keith Chappelle led the comeback effort, catching two touchdown passes in the second half. Chappelle broke an Iowa single-game record with 191 receiving yards and tied another with 11 receptions.
Northwestern
On October 18, Iowa defeated Northwestern, 25–3, before a homecoming crowd of 59,990 in Iowa City. In his first game as Iowa's starting tailback, Phil Blatcher rushed for 148 yards on 19 carries, including a 51-yard gain on a Statue of Liberty play, and also caught a touchdown pass.
at Minnesota
On October 25, in the annual battle for the Floyd of Rosedale trophy, Minnesota defeated Iowa, 24–6, before a crowd of 58,158 in Minneapolis. Iowa fumbled eight times, gave up eight sacks, and managed to score only two field goals. Marion Barber, Jr. scored three rushing touchdowns for Minnesota.
Wisconsin
On November 1, Iowa defeated Wisconsin, 22–13, in Iowa City. In his first game as Iowa's starting quarterback, Pete Gales completed nine of 22 passes for 161 yards and rushed for 41 yards. One of Gales' completions was good for 54 yards and a touchdown to Keith Chappelle. Iowa scored another touchdown when Iowa linebacker Andre Tippett forced a fumble by Wisconsin quarterback John Josten, and Mark Bortz recovered the ball in the end zone.
at Purdue
On November 8, #17 Purdue defeated Iowa, 58–13, at Ross–Ade Stadium in West Lafayette. Mark Herrmann set a Purdue single-game record with 439 passing yards. Hermann also set an NCAA career record with 1,151 pass completions.
Ohio State
On November 15, Ohio State easily defeated Iowa, 41–7, in Iowa City. Art Schlichter threw two touchdown passes, and Calvin Murray rushed for 183 yards to lead the Buckeyes.
at Michigan State
On November 22, Iowa shut out Michigan State, 41–0, before a disappointed crowd of 55,123 fans at Spartan Stadium in East Lansing. After the game, Iowa coach Hayden Fry called it a "real fine victory," while Michigan State coach Muddy Waters said: "You saw it – rotten, lousy flat. It was about the worst game I ever saw. We were afraid it would happen, scared to death it would happen with an inexperienced team like we have."
