Nathan Kirby allowed eight of Vanderbilt's nine runs in the third inning and a late UVA comeback was not enough as Virginia fell to the Commodores, 9-8, in the opening game of the championship series.
This is the Cavaliers' first loss at this year's College World Series.
Virginia got on the board early when Derek Fisher hit a single to right field to score Branden Cogswell and Joe McCarthy.
The Commodores (50-20) can win their first national championship in a men's sport with a win Tuesday night.
Tyler Campbell continued his improbable breakout for the Commodores, doubling twice in the third inning. His second double came off reliever Whit Mayberry with the bases loaded to put Vanderbilt up 9-2.
But Virginia (52-15) chipped away, scoring three runs in the third, two in the fifth and another in the eighth to make it a one-run game.
Adam Ravenelle came on in the ninth to get the last three outs for his second save of the CWS.