Nebraska (4-3, 1-2 Big 12) broke a three-game losing streak and avoided its first 0-3 start in conference play in 63 years. It was just the second victory for the Cornhuskers in their last 10 Big 12 games.
Iowa State (2-5, 0-3) lost for the fifth straight time but had a chance to get back into it after trailing 21-0 at halftime.
Alexander Robinson ran 67 yards for a touchdown on the second play of the third quarter to finally give the Cyclones some life. But they had to punt on their next two possessions, Grant Mahoney missed a 40-yard field goal attempt and their final hopes ended when Devin McDowell fumbled the ball away returning a punt.
Nebraska capitalized with Ganz's 1-yard sneak for a touchdown to put it out of reach.
Ganz was almost flawless in the first half when it looked as if he and his receivers were playing catch in the backyard, going 21-of-26 for 283 yards. He finished 27-of-37 with no interceptions, his sixth 300-yard game in 10 career starts.
Ganz passed Vince Ferragamo, Turner Gill and Tommie Frazier to move into fifth place on Nebraska's career passing list with 3,524 yards.
In the last two games, quarterbacks have completed 79 percent of their passes against Iowa State -- 48-of-61. Baylor's Robert Griffin was 21-for-24 in a 38-10 victory over the Cyclones a week ago.
Nebraska scored on first-half drives of 92, 85 and 71 yards while Iowa State struggled to run any kind of successful play at all. The Cornhuskers led 21-0 before Iowa State got its second first down, which came with 2:09 left in the half.
Ganz was 14-of-15 for 193 yards on the three drives, including a 19-yarder to Nate Swift for the first touchdown. Swift, who had eight catches for 112 yards, caught the ball at the 5, bounced away when defensive back Leonard Johnson tried to push him and dove into the end zone.
Consecutive 11-yard completions to Todd Peterson and Swift set up the second TD, Lucky taking an option pitch from Ganz and zipping in from 15 yards.
The next time the Cornhuskers got the ball, Ganz bailed them out of a second-and-17 hole at his own 22 with a 27-yard completion Roy Helu Jr., who did most of the work himself after catching a short dump-off pass. Lucky finished that drive with a 4-yard TD run on an direct snap.
Only a fumble deep in ISU territory prevented Nebraska from making it 28-0 at halftime. Iowa State's Brandon Hunley jarred the ball from receiver Menelik Holt at the 10 and the Cyclones' Jesse Smith plucked it out of the air.
Even on that drive, which started with 1:08 left in the half, Nebraska totaled 59 yards. Iowa State managed only 45 yards in the entire half despite starting two possessions in Cornhusker territory.
The Cyclones finished with a season-low 218 yards and were 2-for-13 on third-down conversions.