Chucky Jeffery poured in a game-high 22 points to go with seven rebounds, as Colorado upended No. 8 Louisville, 70-66, on Friday night at Coors Events Center.
Arielle Roberson donated 13 points, while Brittany Wilson and Jen Reese added 11 points apiece for the Buffaloes (9-0), who improved to 6-0 at home this season.
The victory was Colorado's first over a top-10 team since knocking off then- No. 5 Stanford in the 2002 Sweet 16.
Antonita Slaughter paced Louisville (9-2) with 19 points and Shawnta' Dyer followed with 14 points in the setback, the Cardinals' second in their last three games after opening the season with eight straight victories.
Louisville trailed by just two, 50-48, with just under seven minutes left in the contest after a pair of Slaughter free throws, but the Buffaloes responded with a 14-3 run to take a 13-point advantage with two minutes left.
The Cardinals countered with the next 10 points to pull within three before four straight Colorado free throws found the margin at 68-61 with 1:06 left.
Slaughter then knocked down a 3-pointer, came up with a steal, and finished a layup off an offensive rebound to make it a two-point game.
Wilson then missed a pair at the line to leave the door open, but Reese corralled the rebound and finished a layup to seal the victory.
Earlier in the game, the Buffaloes used an 11-0 run midway through the first half to help build a 36-30 edge at halftime.