Luke Hancock and Montrezl Harrell had 14 points apiece for the Cardinals (17-3, 6-1 American Athletic Conference), who shot 52.2 percent from beyond the 3-point arc and just under 51 percent overall.
South Florida (10-9, 1-5) lost to a ranked opponent for the second time in less than a week, shooting just 36 percent from the field. The Bulls, coming off a seven-point loss to AAC leader Cincinnati, turned the ball over 23 times while allowing Louisville to outscore them 35-6 off miscues.
Chris Perry led USF with 10 points before fouling out. Victor Rudd was limited to six - nine below his team-leading average - on 3-of-8 shooting.
Hancock made four 3-pointers. Blackshear went 3 for 4 from behind the arc, and Louisville was 12 of 23 overall.
Russ Smith scored 12 points and Mangok Mathiang had 10 to join Blackshear, Hancock and Harrell in double figures. Harrell also grabbed 10 rebounds and blocked two shots.
With point guard Anthony Collins sitting out a ninth straight game because of a sore left knee, USF struggled to find any rhythm on offense.
The Bulls missed 11 of their first 13 shots and Louisville used an 18-3 run to build an early 22-7 lead. It was 45-22 at halftime, and the closest USF got after the Cardinals scored the first seven points of the second half was 27.
Louisville's biggest lead was 44 with just more than 5 minutes left. USF shot 33 percent in the opening half and only warmed up slightly after the break, finishing 16 of 44 (36.4 percent).
The Cardinals have won four straight, and six of seven since losing at Kentucky on Dec. 28. They improved to 28-4 against USF, including 14-1 under coach Rick Pitino.
This story will be updated with other stories from the game: