Ross Neltner had 15 points for the Commodores (21-4, 6-4 SEC), who posted their biggest margin of victory in the all-time series with Kentucky.
Vanderbilt has won four in a row.
Ramel Bradley had 21 points for Kentucky (12-10, 6-3), which hit only three of 15 field goal tries in the first half.
The Wildcats had a four-game winning streak snapped and suffered its worst loss in SEC history.
It was the worst loss for the Wildcats since a 150-95 beating by Kansas on Dec. 9, 1989.