One of five active Hall of Fame coaches and among four in the Atlantic Coast Conference, Pitino is 700-245 overall and 346-117 in 14 seasons with the Cardinals.
Chris Jones added 11 points, and freshman Chinanu Onuaku blocked seven shots for the Cardinals (5-0), who needed a lot of defense to put away the determined Vikings two nights after beating Savannah State by 61 points.
Cold shooting and missed free throws by Louisville allowed Cleveland State (2-3) to stay close throughout and trail just 33-29 with 12 minutes remaining.
But the Vikings made just two of their next 14 shots after that, and the Cardinals pulled away despite their lowest scoring output this season.