Creighton improved to 7-3 on the year, while Vanderbilt dropped to 6-6 in its sixth one-run contest of the year.
The Blue Jays jumped out to a 3-0 lead in the first courtesy of Chris Gradoville's two-run single and Chase Odenreider's RBI single off of starter Ty Davis.
The Commodores scored a run in the bottom of the first on a passed ball by catcher Chris Gradoville that allowed Pedro Alvarez to score from third.
Creighton added two more runs in the second on another Gradoville single to push the lead to 5-1. He had two hits and four RBIs to lead the Blue Jays.
First baseman Ryan Flaherty's sacrifice fly RBI in the bottom of the second made it 5-2. Pedro Alvarez' RBI single in the fifth cut the lead to 5-3 and Dominic de la Osa's RBI double in the eighth sliced the advantage to just a run.
Ambidextrous reliever Pat Venditte (1-0) picked up the win for the Blue Jays after allowing one run on four hits in three innings of work. Scott Reese closed out the game with two scoreless innings to pick up the save.
Ty Davis (3-2) was charged with the loss after giving up all five CU runs in two innings of work. Cameron Betourne pitched five innings of one hit relief and was followed by Tyler Rhoden and Nick Christiani who each hurled a scoreless inning apiece.
"That was a tough game to lose," said head coach Tim Corbin. "I thought the bright spots were the way Betourne (Cameron) pitched and offensively we were a little bit better tonight."
Vanderbilt will host Brown this weekend in a three-game series starting on Friday at 4 p.m. The Bears are 0-3 after getting swept by Florida State in Tallahassee last weekend.
Creighton 320 000 000- 571 Vanderbilt 110 010 010- 494
Mancuso, Venditte (5), Reese (8) and Gradoville. Davis, Betourne (3), Rhoden (8), Christiani (9) and Hernandez. W- Venditte (1-0), L- Davis (3-2). SV- Reese (1). HR- None.