The Cardinals, winners of 10 of their last 12 games, fell 69-67 to Connecticut Monday night in Hartford.
Huskies guard A.J. Price paced UConn with 20 points.
"We felt that at this particular point, Rick's team was a bad match for us," said UConn's Jim Calhoun. "With only two regular guards to play it was a difficult situation for us.
"These guys, the character they displayed makes me proud that they wear the uniform that says "Connecticut" on it. I'm exceptionally proud of them."
Playing without two of their top guards – Jerome Dyson and Doug Wiggins – Connecticut won their fourth game in a row. The win moved UConn into a tie with Louisville for third place in the Big East standings at 5-3 overall.
Louisville, which trailed by as many as 10 in the second half, had an opportunity to win or tie the game on the final possession but Juan Palacios missed a step-back three-pointer from the top of the key at buzzer.
"We just told Sosa to create," Rick Pitino said of the final shot. "We had a number of options. We weren't necessarily looking for a three, we were just looking for a good shot. And we scored on it the last three out of four times. Sosa was playing real well. He finally understood how to play this game tonight, which is great to see."
Palacios, who hit 3 of 9 three-pointers and grabbed four rebounds, led Louisville with 16 points.
Despite shooting just 29 percent from the floor in the first half, Louisville managed a 30-30 tie at the break. The Cardinals settled for three's in the first half despite foul trouble for UConn's 7'3 center Hasheem Thabeet. Louisville was 5 of 20 from three-point range in the opening frame.
For the game, Louisville made just 24 of 60 shots, 40 percent. The Cardinals also made only 8 of 14 free throws, 57 percent, including three crucial misses down the stretch by Edgar Sosa and David Padgett when Louisville trailed by four.
"You have to make threes against Connecticut because they'll give you a lot of threes because of their shot-blocking ability," Pitino said. "You've got to make them. Providence came in here and made them, Cincinnati made them at Cincinnati, and teams that don't make them don't win.
"We moved the ball constantly. In the first half the shots just wouldn't fall, but I'm proud of our guys. They gave great effort and did a lot of good things."
The other big stat: Connecticut dominated Louisville on the glass 40-29. UConn forwards Stanley Robinson and Jeff Adrian both hauled in 10 boards.
The Huskies also enjoyed a 30-16 scoring advantage in the paint. The 6'9 Robinson scored 16 points, while Adrien chipped in 12. Thabeet contributed nine points and three blocked shots.
David Padgett was the only other player to score in double-figures for Louisville. Padgett finished with 12. Terrence Williams and Edgar Sosa both scored seven points, while Andre McGee, Jerry Smith and Derrick Caracter each had six.
Louisville next takes on Rutgers at home this Saturday at 3 p.m. The Cardinals defeated the Scarlet Knights earlier this month 69-54.