The Cardinals (11-5, 1-1 Big East) rebounded from losing their conference opener 78-62 at Notre Dame, while South Florida (9-8, 0-3) has lost 18 of 19 Big East games since entering the league last season.
Jenkins made 5 of 6 six shots, including all four of his 3-point attempts, and scored eight straight points to thwart South Florida's last push to get back in the game early in the second half.
Edgar Sosa had 12 points and David Padgett and Jerry Smith added 11 apiece for Louisville, which started three guards and two forwards with Juan Palacios, the Cardinals' top frontcourt player, sitting out with an injury.
South Florida was held to a pair of field goals by Gransberry in the first seven minutes of the game and never fully recovered.
The Bulls trimmed a 10-point deficit to six late in the first half, however Louisville answered with Chris Current's 3-pointer and two free throws by Padgett to rebuild the lead to double figures.
It was 27-19 at the half, and the closest South Florida would get the rest of the way was four.
Jenkins made 3-pointers on consecutive trips down the floor, then added a layup for an eight-point burst that helped Louisville pull away for good. Smith also had eight points and Williams and Will Scott contributed 3-pointers to finish a 22-7 surge that built the Cardinals' lead to 52-33.
Louisville made 13 3-pointers and shot 53 percent overall. South Florida shot 42 percent and was held to three field goals in the final eight minutes.