Tech (11-3, 1-1 Big 12) shot just 28.9 percent from the field (17 of 57), needing just one more shot to fall in the final 20 seconds.
Junior Kelsi Baker hit two free throws to bring Tech within one at 55-54, then forced a steal by Christine Hyde on the next possession by Iowa State. As senior Monique Smalls drove the lane, her floater went just wide and Iowa State closed it out with a free throw and jumper by Chelsea Poppens.
Iowa State (11-1, 2-0) won its first game in Lubbock since Feb. 8, 2009 (59-52).
Senior Chynna Brown led Tech for the second consecutive game with 19 points, hitting 4 of 9 from behind the arc, which is also where Iowa State found its success early on.
The Cyclones took their largest lead on a 9-0 run, hitting five threes to start the game and eight total in the first half.
Senior Casey Morris hit her first of three treys near the 16-minute mark of the first half to eclipse the 1,000-point mark for her career. She becomes the first Lady Raider to do so since Kierra Mallard accomplished the feat in 2011.
Tech will face Kansas State (10-4, 1-1) at 7 p.m. CT on Wednesday at United Spirit Arena. The game will be televised nationally on FOX College Sports.