Kirk Hinrich and Nick Collison left their home state with a win.
No Kansas player, let alone the two starters who hail from Iowa, had experienced winning at Iowa State since 1998 until Wednesday night.
Drew Gooden had 23 points and 11 rebounds, and the second-ranked Jayhawks beat the Cyclones 88-81 to break a five-game losing streak against them.
"We feel good for Nick and Kirk more than anything," Kansas coach Roy Williams said. "At the same time, we feel good for this team this year because it was a big win for us and a great last minute and a half."
Kansas (16-2, 5-0 Big 12) built a 12-point lead early in the second half, fell behind by four, then pulled out the victory with some clutch shooting and defense.
NO. 3 MARYLAND 85, NO. 21 WAKE FOREST 63: Juan Dixon and Steve Blake each scored 19 points for the Terrapins (15-3, 5-1 Atlantic Coast Conference), who won their sixth straight over the Demon Deacons.
Darius Songaila had 14 points and 10 rebounds for Wake Forest (13-6, 3-3).
NO. 9 ILLINOIS 80, WISCONSIN 48:Cory Bradford scored all of his 16 points in the first half for the Illini (15-4, 4-2 Big Ten), who finished 10-of-20 from 3-point range in winning their 28th straight at home.
ARIZONA ST. 88, NO. 10 ARIZONA 72:Chad Prewitt scored 22 points, and Curtis Millage added 19 as the Sun Devils (11-7, 4-5 Pac-10) beat Arizona for the first time in 11 games, a streak dating to 1995.
NO. 11 OKLAHOMA ST. 70, NEBRASKA 63: Ivan McFarlin set career highs with 20 points and 17 rebounds as the Cowboys (16-3, 3-3 Big 12) snapped a two-game losing streak.
NO. 15 GEORGIA 81, ARKANSAS 67:Jarvis Hayes had 21 points for the Bulldogs (16-3, 5-1 Southeastern Conference), who matched last season's victory total with the home win.
TEXAS A&M 80, NO. 24 TEXAS 74:Bernard King scored 30 points for the Aggies (8-11, 2-3 Big 12), who won at Austin for the first time since 1987 and snapped a 16-game losing streak to the Longhorns that dated to 1994.
NO. 25 CONNECTICUT 75, ST. JOHN'S 70: Johnnie Selvie had 16 points and the Huskies (13-3, 6-0 Big East) were able to overcome 19 turnovers to remain the conference's only unbeaten team.