The Wildcats (10-4) also seemed to get a bit of help from officials in the final seconds.
Nerlens Noel hit a jumper with 17.3 seconds left that went in after the shot clock buzzer went off, and Vanderbilt coach Kevin Stallings took a timeout to plead his case. Officials didn't review the play. Kedren Johnson made a 3 with 7.6 seconds left to pull Vandy within 60-58, and Kyle Fuller stole the inbound pass with 6.7 seconds to go giving Vandy a last chance.
But Johnson's 3 hit the rim just before the buzzer as the rally fell short for Vanderbilt (6-7).
Ryan Harrow led Kentucky with 16 points, Noel had 13 and Archie Goodwin 12.
Johnson finished with a game-high 18 points, and Rod Odom added 12 as Vanderbilt outrebounded Kentucky 42-37.
This was a rematch of the SEC tournament championship game that Vanderbilt won last March for its first such title in 61 years. Wiltjer is one of only five players combined on the rosters left from that game, and all the youth is why neither team was ranked in this game for the first time since Feb. 17, 2009.
Kentucky coach John Calipari started his latest crop of freshmen for a second straight game, and the Wildcats looked good in taking the lead from the opening bucket and leading 35-24 at halftime. Vanderbilt had won six of the previous nine games against Kentucky in Memorial Gym, and the Commodores finally stymied Kentucky when they went to a zone defense.
The Wildcats missed 12 straight shots from the floor. Vanderbilt took advantage, trailing 47-31 with 13:48 left when Sheldon Jeter hit a jumper to start an 18-0 run.
Shelby Moats hit a 3, and Dai-Jon Parker added a 3 to get the Commodores rolling. Kentucky went cold too, missing 12 straight shots from the floor. Johnson's driving layup tied it up at 47, and Jeter's dunk capped the run and gave Vanderbilt its first lead of the game at 49-47 with 6:11 left.
The teams swapped the lead twice with three ties down the stretch. Johnson's bucket for Vandy tied it for the last time at 54, then Wiltjer's long jumper put Kentucky ahead to stay to set up the frantic ending.
Kentucky won its SEC opener for the 23rd time in 26 seasons, improving to 62-18 all-time.
All the practice since Kentucky's easy 90-38 win over Eastern Michigan sure paid off early. Harrow hit a 3-pointer within the first 90 seconds, and the Wildcats dominated Vanderbilt early.
Vanderbilt came in scoring 37.3 percent of its points off 3-pointers, and the Commodores missed their first 10. Their shooting woes extended all over the court as they also missed easy layups when they did get close enough to the basket to shoot. Kentucky disrupted them repeatedly, blocking six shots alone in the first half.
The Commodores didn't hit a 3 until 1:22 remained in the first half when Johnson hit from beyond the arc, and Odom added another just before halftime. Vanderbilt wound up hitting 8 of 30 from 3-point range.