Though Louisville tried to slow the tempo and keep the game close, UConn had too much firepower for the upstart Cardinals.
Louisville stayed close early in the contest but Tina Charles had 15 points and 12 rebounds in the first half to give UConn a comfortable 39-25 lead.
"This one is going to be really special the way we did it," Connecticut coach Geno Auriemma said.
Angel McCoughtry kept Louisville in contention early in the game. The Cardinals All-American scored 11 quick points to help Louisville keep pace with a 17-17 tie ten minutes into the game.
But McCoughtry failed to score in the final 10 minutes of the first half and the Cardinals made just three field goals during that span as the Huskies opened a commanding lead.
UConn closed the first half on a 22-8 run. The Huskies came out of the break intent on putting the Cardinals away quickly.
The Huskies opened the second half with a 7-0 run to take a 46-25 lead and never looked back. Louisville missed their first eight shots out of the break as UConn put the game out of reach.
Louisville cut the margin to 57-40 with eight minutes left but couldn't get any closer.
When Deseree Byrd fouled out with six minutes left, UConn extended their lead to finish off the Cardinals.
In her final game for Louisville, McCoughtry finished with 23 points and six rebounds but made just 9 of 24 shots.
Candyce Bingham chipped in 10 points and 10 rebounds. Monique Reid added seven points and Becky Burke had five points for the Cardinals.
Tina Charles led UConn with 25 points and 19 rebounds. Renee Montgomery added 18 points while Maya Moore had 18 points and nine boards.
UConn finished a perfect season 39-0. Louisville ended the best season in school history with a 34-5 mark.