Taking up the slack with leading scorer Samardo Samuels on the bench in foul trouble much of the game, Clark made 8 of 18 shots and finished with a team-leading nine rebounds. Edgar Sosa added 12 points for the Cardinals (10-3, 1-0).
Dominique Jones led South Florida (5-9, 0-2) with 11 points, but missed 9 of 10 shots from the field and was not on the floor at the end when Bulls reserves scored 10 points in the final 1:03 to make the final score look a little more respectable.
The Cardinals entered the conference opener on an emotional high after beating Kentucky 74-71 on Sosa's long 3-pointer in the closing seconds on Sunday. They've won eight straight over South Florida and lead the series between the former Conference USA members 22-3.
The team's arrival in Florida was delayed Tuesday after its plane returned to the Louisville airport after pilots received a warning message in the cockpit that indicated a fire on board. The warning turned out to be false, and the Cardinals took another plane that got into Tampa shortly after 11 p.m.
With Samuels and Terrence Williams on the bench with two fouls, Louisville rode a 19-4 run to a 28-15 lead. USF whittled its deficit to 32-26 at the half, but the closest the Bulls got after the break was five.
It was 49-41 with just under 12 minutes to go, but Williams made a dunk and a layup -- his only baskets of the game -- during a 14-4 surge that enabled the Cardinals to pull away for good. The lead was 68-47 when Louisville emptied its bench, with the exception for Samuels, who finished with nine points on 3-of-4 shooting in 23 minutes.
USF has dropped eight of its last 10 games and drooped to 8-76 all-time against ranked opponents. The Bulls dropped their conference opener 59-54 to Syracuse and is 7-45 in league play since moving from C-USA to the Big East in 2005.
Augustus Gilchrist came off the bench to score 11 points for South Florida, which hurt its cause by going 14-for-29 from the foul line.