The Cyclones led most of the way and put the game out of reach at the end of a 10-2 run midway through the second half, capped by Royce White's dunk, to lead 48-31.
Iowa State (14-5, 4-2) took advantage of Texas Tech turnovers, converting the Red Raiders' 15 errors into 21 points. The Cyclones got another 34 inside, as White dished the ball to teammates when the defense collapsed around him.
Iowa State, third in the Big 12 in 3-point percentage, hit 8 of 25 from beyond the arc.
Robert Lewandowski tied his career high with 20 points to lead Texas Tech (7-11, 0-6).
The Red Raiders last lost their first six conference games in 2000.