Candyce Bingham added 12 and Keshia Hines had 10 for Louisville (25-3, 12-2 Big East), which is off to its best start after 28 games in school history. The Cardinals shot 57 percent (27-for-47) from the field.
Laura Kurz scored 18 points and Maria Getty added 10 for Villanova (17-10, 9-4), which has dropped two straight after reeling off a seven-game winning streak. Its the second consecutive loss to a ranked team since falling 70-54 at No. 19 Pittsburgh last Wednesday.
The Wildcats are 2-4 against ranked teams and are in a stretch of four games in a row against ranked teams. They travel to top-ranked and undefeated Connecticut on Tuesday.
Villanova got within 42-38 on a 3-pointer by Siobhan OConnor with 13:18 remaining.
Louisville responded with a 10-0 run, including eight straight points by McCoughtry, to take a commanding 52-38 advantage with 10:44 left.
McCoughtry, who scored at least 30 points for the sixth time this season, scored in various ways by hitting a 3-pointer, scored inside and then added a three-point play as the Cardinals pulled away.
Louisville led by as many as six points in the first half.
Villanova rallied hitting five 3-pointers to keep the game close while the Cardinals didnt attempt one from beyond the arc.
Louisville leads the all-time series against Villanova 4-0.
