Asia Durr scored 14 of her 24 points in the second quarter, Dana Evans added 20 points and No. 3 Louisville held No. 2 Connecticut to 38 percent shooting in a 78-69 victory Thursday night at home before an announced 17,023.
The game drew the largest crowd for a women's basketball game so far this season.
After starting 0-for-4 from the field in the first quarter, Durr made three consecutive threes to open the second and put the Cardinals (20-1) up 32-24.
"I had great looks, even when the ball didn't go in," Durr said.
Evans scored 12 points in the second half, hitting a three-pointer with just under two minutes left for a 70-59 lead, to help Louisville end a 17-game losing streak in the series.
Jazmine Jones and Sam Fuehring followed with two free throws each for a 13-point lead and the Cardinals added four more from the line in the final 1:30 to seal their first series victory against UConn (18-2) since their inaugural meeting in the 1993 NCAA tournament.
Jones had 13 points and 12 rebounds, and Fuehring added 10 points and 12 rebounds.
Napheesa Collier had 20 points and Crystal Dangerfield 19 for the Huskies, who had won seven in a row since losing at current No. 1 Baylor.