The Gosport talent was on target twice in the second half at Furze Lane, after Owen James had opened the scoring for the visitors before the interval.
The hosts started the game well and almost led after three minutes when Matt Casey met Freddie Read’s corner, but the defender was unable to direct his header on target.
In the 11th minute, Lethbridge had an angled right-footed effort saved by U’s goalkeeper Niall Clayton, before Oscar Johnston missed a gilt-edged opportunity from close range.
However, it was Oxford who broke the deadlock on 22 minutes.
James found space inside the Blues box and his right-footed effort trickled inside the far post.
Mark Kelly’s side almost went into the break on level terms when James Whiting forced a decent stop from the U’s shot-stopper on the stroke of half-time.
Nevertheless, Pompey had to wait just 12 minutes after the restart to equalise.
Johnston’s driving run opened the Oxford defence up before Mayes showed superb vision to pick out Lethbridge at the far post and the striker remained composed to steer a right-footed volley home.
And seven minutes later the Blues were in front.
Haji Mnoga had a header from a corner saved but Kelly’s men kept up the pressure and got their reward.
Mayes had a close-range shot kept out by Clayton but Lethbridge was first to the rebound to finish into an empty net.
The first-year scholar almost notched a hat-trick eight minutes from time when his header was well saved by Clayton before Mayes’ follow-up cannoned off the far post.
The young Blues dealt with Oxford’s late pressure well and it was a deserved three points for Kelly’s side.