Guard Cameron Clark, who had a fierce start, led OU with 16 points, but it wasn't near enough.
Hot 3-point shooting again for the Cyclones, mirroring the first meeting between the two when the Sooners surrendered a program record 15 3-pointers, allowed them to expand a double-digit lead in the first half.
They carried a 37-28 advantage into intermission and built it to as much as 21 with six minutes remaining.
Carl Blair, who provided a nice 12-point boost off the bench, scored five consecutive points after ISU forward Melvin Ejim was ejected from the game for a flagrant two foul and that brought OU back within 12.
But they couldn't get much closer than that the rest of the way.
ISU guard Scott Christopherson led all scorers with 25 points, converting 5-for-8 from downtown and 9-of-15 shots overall.
Guard Chris Allen, center Percy Gibson and Ejim all also finished in double figures, with 16, 11 and 10, respectively.
For the Sooners, five players actually finished in double figures, including Blair and Clark, along with guard Sam Grooms and forwards Romero Osby and Tyler Neal, who notched 12, 10 and 10, respectively.
But leading scorer, guard Steven Pledger, netted just seven points.
ISU dominated OU on the boards, out-rebounding the Sooners 40-28.
The Sooners shot it well, 43.5 percent, but the Cyclones were that much better at 51.9 percent.
OU, losers of six in a row, will again try to get back on track when it hosts Oklahoma State at 7 p.m. Wednesday inside Lloyd Noble Center.