Peyton Siva had 11 points, six rebounds and five assists for the Cardinals (2-0), who pulled away in the final 10 minutes after the Tigers moved within 39-35.
Jackson State (0-4), playing its fourth straight road game to open the season, made Louisville work for it. Jenirro Bush led the Tigers with 16 points and Grant Maxey added eight points as Jackson State forced the Cardinals into 19 turnovers.
It just wasn't quite enough. Jennings and Knowles led a late Louisville surge as the Cardinals shook off any hangover from a season-opening upset of No. 16 Butler on Tuesday.
Louisville coach Rick Pitino said Friday he wasn't worried about a letdown following the emotional win over the Bulldogs, believing his team was too young and inexperienced to get caught up in the hype.
Maybe he should have been concerned.
The Cardinals slogged through an uninspired first half, the crispness they displayed against the Bulldogs long gone. Louisville had six turnovers in the first 4 minutes and struggled to play under control.
The backcourt, particularly Siva, Knowles and freshman Elisha Justice, had trouble holding onto the ball. There was little flow, thanks in part to a Jackson State defense that made Louisville work to get open looks.
Still, the Cardinals were able to build a 30-16 halftime lead behind their defense, which held Jackson State without a field goal for over 6 minutes at one point and harassed the Tigers into 19 percent shooting.
Louisville extended the lead to 39-21 early in the second half before Pitino went to his second unit hoping to get some experience.
It didn't quite work. Jackson State went on a 14-0 run as the Cardinals bumbled their way through possession after possession. A layup by Bush cut the lead to 39-35 and forced Pitino to call timeout while he sent the starters back in.
Knowles got the Cardinals going with a layup and Mike Marra drilled a 3-pointer off a nice feed from Siva. Jennings added a free throw and Siva converted a steal into a bucket to extend the lead to 47-35.
A runner by Maxey got Jackson State within 47-39, but the Cardinals went on an 11-2 burst highlighted by a Mike Marra dunk to create some breathing room against the well-traveled Tigers.
Jackson State, a member of the Southwestern Athletic Conference, is in the midst of a seven-game road trip to start the year and has proven to be a tough out.
The Tigers hung around all game in a 63-49 loss to No. 17 Baylor on Thursday, forcing the Bears into 26 turnovers. They were just as effective against the Cardinals, not allowing Louisville to push the tempo and play at the frantic pace preferred by Pitino.
Yet the Cardinals had enough at the end to remain perfect in their new downtown arena. Louisville hosts Chattanooga on Monday.