Prescott completed a career-high 23 of 34 passes and also rushed for 33 yards. Jameon Lewis had a 19-yard touchdown run, caught a 17-yard scoring pass and also threw the 17-yard touchdown to Prescott on a trick play.
Mississippi State (4-3, 1-2 Southeastern Conference) beat Kentucky (1-6, 0-4) for a fifth straight season.
It's the second time this season Lewis has had rushing, receiving and passing touchdowns in a game.
Kentucky's Joe Mansour made a 44-yard field goal with 8:15 remaining to pull the Wildcats to 28-22, but the Wildcats could get no closer.
Kentucky's final drive was stopped at Mississippi State's 29 when Maxwell Smith's fourth- down pass fell incomplete.
Kentucky pulled to 21-19 in the third quarter on Jojo Kemp's 14-yard touchdown run. Then in what proved to be a key moment, the Wildcats recovered an onside kick, only to have it disallowed because of an offsides penalty.
Mississippi State took advantage. A 74-yard drive ended on the halfback pass from Lewis to Prescott, who handed the ball off before leaking into the open field for the catch, touchdown and 28-19 lead.
Prescott continued his breakout season with another complete performance. The 6-foot-2, 230-pound sophomore completed 11 of 18 passes for 160 yards and two touchdowns in the first half, helping Mississippi State to a 21-10 halftime lead.
Prescott's first touchdown pass — a 60-yard fling to a wide open Malcolm Johnson — came after he danced out of the pocket while avoiding a sack. Kentucky's defense shifted forward because of Prescott's ability to run, and it gave Johnson time to slip behind the secondary undetected.
The Bulldogs had 296 total yards in the first half. Mississippi State started the game with the intention of using two quarterbacks, but Tyler Russell appeared to suffer an ankle injury on his first series and never returned.
Kentucky's offense had a few good early moments — especially on a 51-yard screen pass from Smith to Timmons that tied the game at 7 — but the Wildcats became predictable because of their inability to throw downfield. Smith has dealt with pain in his throwing shoulder all season and wasn't close on most of his attempts to complete long passes.
Mississippi State safety Nickoe Whitley was ejected in the second quarter after earning two personal foul penalties over a span of four plays. The extra 30 yards greatly aided Kentucky on a drive that ended on a 45-yard field goal by Mansour.
Kentucky's Smith completed 18 of 33 passes for 160 yards and one touchdown. Raymond Sanders had 86 yards rushing.