Freshman Breanna Stewart led the powerhouse Huskies (35-4) with 23 points and nine rebounds, and Kaleena Mosqueda-Lewis scored 18 points, including five 3-point baskets.
The win gave UConn its eighth NCAA women's championship. It was also the eighth national title for head coach Geno Auriemma, who moved into a tie for the NCAA lead in career championships with Tennessee's legendary Pat Summit.
Stewart keyed a 19-0 run by the Huskies, who surged to a 29-14 midway through the first half. UConn was in control 48-29 at halftime and outscored the Cardinals (29-9) by six points in the second half.
Sara Hammond scored 15 to lead the Cardinals. Louisville has lost its last 13 games against UConn.