A two-run single by Bryan Reynolds lifted the No. 12 Commodores (28-7, 9-5 SEC) to victory at Hawkins Field in Nashville.
No. 16 Kentucky (22-12, 8-6 SEC) had rallied ahead in the top of the eighth inning and appeared poised to even the weekend series at a game apiece.
UK starter Dustin Beggs continued his string of exceptional starts, allowing only one run on four hits and no walks. He exited in the eighth inning with a 2-1 lead, but Zach Strecker (2-1) was unable to hold the lead out of the Cats' bullpen.
Vandy's Kyle Wright also took a no-decision despite a great starting effort. He allowed just one earned run over seven innings before Matt Ruppenthal (3-1) picked up the win in the decisive eighth inning. Ben Bowden took over in the ninth, notching his seventh save of the year for the Dores.
Jason Delay powered the Vandy offense early on with a solo home run in the fifth inning off Beggs.
Catcher Kole Cottam had two of UK's seven hits on the day.
The series will conclude on Sunday at 2 p.m. ET at Charles Hawkins Field.