Danny Hylton opened the scoring from the spot but the Blues turned the game on its head with second-half goals from Paul Hayes and Peter Murphy.
However, Hylton had a chance to level it in stoppage time but blasted another penalty over the bar to secure Wanderers' place at the summit.
Paris Cowan-Hall was unable to shake off the injury he sustained last week so Matt Bloomfield took his place in the starting line-up, while the home side remained unchanged after a recent upturn in performances.
Peter Murphy had the game’s first chance, meeting Paul Hayes’ dinked cross with a header which keeper Ryan Clarke held on the line inside the first four minutes.
Alfie Mawson had the home fans on their feet with a late tackle in the middle of the park which had them baying for a red card, but the referee judged a yellow was sufficient.
Oxford’s first chance arrived after 16 minutes when Danny Hylton beat the offside trap to tear away down the left and after jinking onto his right foot, his near post shot was comfortably saved by Matt Ingram.
But action quickly swung back to the other end when Hayes delivered a low pass across the box which was met by a good first touch by Steven Craig, but he dug his shot over the crossbar from 15 yards.
Then Josh Scowen struck wide after Joe Jacobson’s cross found its way to Matt Bloomfield, who tapped the ball back into the path of his fellow midfielder.
Oxford clearly wanted to play the ball out from the back but Wanderers’ high pressing game wasn’t allowing them to do so, forcing them into some nervy moments along the defence.
However, it was the home side who broke the deadlock when Hylton and Jacobson tangled in the box and after the referee opted to award a penalty, Hylton found the net even though Ingram went the right way.
It instilled a new-found confidence in the hosts who enjoyed a more settled period than they’d been afforded previously, although Wycombe did finish the half well with some dangerous balls into the box.
It was the same story at the start of the second period, when Aaron Pierre’s bullet header was blocked en route to goal before Jacobson’s free-kick was cleared from inside the six-yard box.
Then Hogan Ephraim was handed his debut when he came on for Steven Craig and it was the former QPR man who started the move which led the equaliser.
Ephraim skipped away down the right to deliver a deep cross which was returned to the six-yard box by Sam Wood. The ball was cleared to Peter Murphy 20 yards out who poked it through to Paul Hayes, who made no mistake from 12 yards.
Suddenly the Blues were rampant, and the turnaround was complete on 63 minutes when the deadly combination of Sam Wood and Peter Murphy combined yet again for the third game running.
A deep cross was met by Wood who beat his man and crossed into the box, finding Murphy who met the delivery with an inch-perfect header to beat Ryan Clarke.
The hosts were rattled, with the Blues playing some of their most ruthless football of the season, although they did have a chance to level when sub James Roberts stayed onside but saw his shot saved by Matt Ingram.
Tyrone Barnett headed harmlessly over before Ryan Clarke denied Hogan Ephraim from a tight angle as the game moved into the closing stages.
And then, just as it did last year, the game saved its biggest drama for stoppage time. Sam Wood was adjudged to have pushed Callum O’Dowda at the back post, but Hylton blasted the resulting spot-kick high into the car park behind the goal.
With that, and Luton drawing at Exeter, Wycombe Wanderers returned to the top of Sky Bet League 2 with a victory in their rivals’ back yard.
Wycombe: Ingram, Jombati, Jacobson, Mawson, Pierre, Bloomfield (Kretzschmar 86), Murphy, Scowen, Wood, Hayes (Rowe 90), Craig (Ephraim 52).
Unused subs: Richardson, Lewis, Walker, McClure.
Oxford: Clarke, Whing, Holmes-Dennis, Mullins, Wright, Riley, Collins (O’Dowda 77), Rose, Potter (Roberts 69), Barnett, Hylton.
Unused subs: Long, Meades, Raynes, Jakubiak, Howard.
Ref: Mr T Robinson
Attendance: 7,552 (1,690 from Wycombe)