The Reds broke open a one-run game with a four-run fourth.
The Americans were noticeably more muted in this one, and all three goals were in the first half.
Two home runs from Vanderbilt's Austin Martin were too much for Louisville to overcome.
Louisville outfielder Jake Snider and assistant coach Eric Snider will spend perhps their first Father's Day together when the Cardinals face Vanderbilt Sunday in the College World Series.
Trainer Bill Mott says the Derby winner will get a "good two-month vacation."
Trainer Dallas Stewart won the Stephen Foster Stakes for the second time.