Stefan Oakes blasted in the crucial goal minutes from time and just seconds after Gavin Johnson appeared to have given Oxford a home replay.
In a physical and quick game the class of Wycombe eventually told and Will Antwi's second-half goal appeared to be enough before a frantic last five minutes in which Wycombe sealed victory.
Oxford, who have yet to lose in the League this season, showed plenty of fight but not enough quality, as they fell at the first hurdle.
Hours after the Carling Cup draw Wycombe put the excitement of an away day at Charlton out of their minds as they hope to embark on an equally long run in the FA Cup.
The game started at a decent pace with Oxford showing plenty of aggression and determination but not getting much of the ball. The first real action came after some neat interplay between Matt Bloomfield and Tommy Mooney, which saw Wycombe earn a free-kick 30 yards out. Oakes stepped up and drilled his shot against the bar.
Wycombe went close again minutes later. The tricky Kevin Betsy got to the by-line and drilled a tempting ball into the box, Oxford keeper Billy Turley just doing enough to steal the ball off the foot of veteran striker Mooney.
Oxford registered their first efforts at the Wycombe goal on 15 minutes but Eddy Hutchinson's header went high and wide.
The game continued to be a battle of Wycombe's neat passing and Oxford's hustle and bustle and Wycombe had another good chance to break the deadlock on 24 minutes but Mooney could only direct an Oakes cross straight at the busy Turley.
Russell Martin was the next man to go close. Chris Palmer produced more step-overs than Cristiano Ronaldo as he beat Eddie Anaclet and put in a decent cross for the defender whose tame header was easily saved.
Despite Wycombe's domination the half ended with two good Oxford chances. Jamie Young had to be alert to tip over Chris Willmott's stinging left-foot volley from 25 yards and, from the resulting corner, Antwi was forced into a goal-line clearance of his own as he headed over.
Oxford, playing towards their own fans in the second half upped their tempo but still couldn't get close to the Wycombe goal.
Wycombe thought they should have been awarded a penalty on 54 minutes in their first venture of the half into the Oxford box when Mooney's flick appeared to hit the arm of Phil Gilchrist. The referee was not convinced though.
Wycombe took the lead soon after though. Antwi got the faintest of touches on a Betsy cross-shot to just deceive the keeper after a short corner.
The goal seemed to deflate the Oxford confidence after a bright start to the second half but they gradually started to pick themselves up and keep hold of the ball but again lacked the creativity to breach the strong Wycombe back line.
The next chance again fell to the Chairboys, the ball kindly falling to Chris Palmer from a corner but he skied his left-foot shot from 10 yards over the stand.
The more the half went on the better Wycombe got, showing no signs of tired legs, despite it being their second Cup game of the week. It should have been game, set and match for Wycombe 10 minutes from time when Antwi somehow blasted wide from five yards after a Bloomfield cross.
Then, from nowhere, Oxford stunned their hosts. A 30-yard free-kick from substitute Gavin Johnson found its way through a crowd of players and into the net via the post.
Oxford, still celebrating what seemed like a game-saving goal, then conceded within seconds, Oakes blasting home from inside the box to seal a deserved victory.