Three second half goals ensured that Oxford United went home from Prenton Park with three points. A brace by Kemar Roofe and a solitary Danny Rose strike after the break gave the U's the win.
Tranmere manager Micky Adams made two changes to the side which started against Mansfield Town with Kayode Odejayi and Iain Hume coming in to replace Cole Stockton and Rory Donnelly who were named on the bench.
Rovers had the first chance of the afternoon in the opening 60 seconds as George Green found Max Power on the left edge of the penalty area but his shot was saved by Jamie Ashdown.
A minute later, Kayode Odejayi headed wide while George Green found the hands of Ashdown with a free-kick from 20 yards all within the opening five minutes of the game.
On the quarter-hour mark, Jennison Myrie-Williams was played in after a quick throw in by Iain Hume but he pulled his shot across goal and wide of the target.
Oxford first sight of goal came on 19 minutes as corner from the left was headed wide by Chey Dunkley 12 yards out.
Midway through the first half, Rob Taylor tried his luck from 30 yards but his powerful driven effort flew narrowly over the crossbar.
Oxford had an opportunity on 36 minutes. Green overhit a left-wing corner and Kemar Roofe picked up the ball and ran 70 yards upfield but his 25 yard shot was wide of Owain Fon Williams' goal.
Five minutes before the interval, Fon Williams was called into action for the first time as Danny Rose fired a shot across the face of goal from the left edge of the area but the Welsh goalkeeper was on hand to make the save.
In the second minute of first half stoppage time, a corner from the left by Green found Donacien who turned the ball towards goal but the Oxford defence cleared the ball off the goal-line as the half ended goalless.
Hylton had the opening chance of the second period as his shot from 20 yards deflected up onto the roof of the net on 46 minutes, before three minutes later Myrie-Williams forced Ashdown into a smart save at his near post.
On 50 minutes, Oxford took the lead as a cross from the right found Roofe who headed home from 10 yards.
It was 2-0 two minutes later as Alex MacDonald found Rose at the near post who steered the ball home.
Rovers made a double substitution on 61 minutes with Jason Koumas and Marc Laird entering the fray in the place of Myrie-Williams and Green.
The visitors increased their lead on 68 minutes as a ball into the penalty area was headed down by Hylton and Roofe curled the ball into the top corner of the net.
Tranmere's final personnel change saw Matt Hill replace Taylor at left back on 71 minutes.
Rose fired wide from 20 yards on 76 minutes before Laird headed a Koumas free-kick into Ashdown's hands a minute later.
With 10 minutes remaining, Koumas cut inside from the right and fired a shot inches past the post before five minutes later firing wide with a free-kick from 25 yards.
Oxford substitute James Roberts almost found the net in second half additional time as he hit the post with his first effort before firing the follow up which forced Fon Williams into an excellent save in the final action of the game.
Tranmere: Fon Williams, Holmes, Donacien, Ihiekwe, Taylor (Hill 71), Myrie-Williams (Koumas 61), Power, Jennings, Green (Laird 61), Odejayi, Hume. Substitutes: Brezovan, Dugdale, Stockton, Donnelly.
Oxford: Ashdown, Skarz, Dunkley, Wright, Rose, Hylton (Roberts 80), MacDonald (Hawtin 89), Ruffels, Collins, Long, Roofe (Hoban 75). Substitutes: Clarke, Mullins, O'Dowda, Whing.
Referee: Andy Madley
Yellow cards: Skarz (83)