Conor McAleny's quick-fire double and Joshua Ruffels' second-half header condemned Millwall to a first home defeat since December on Saturday afternoon at The Den.
McAleny scored in the sixth and ninth minutes to ease the visitors into a two-goal lead, with Ruffels heading past Archer in the second-half to seal the victory.
Three changes were made from the starting XI that fell to defeat at Fleetwood Town on Easter Monday, with Jordan Archer, Tony Craig and Jake Cooper returning to the team in place of Tom King, Joe Martin and the injured Shaun Hutchinson.
After six minutes, the first chance of the game resulted in the visitors taking the lead. Neat play between John Lundstram and Marvin Johnson teed up McAleny, who drove low past Archer from around 20-yards out.
Just three minutes later, The U's found themselves two to the good. More clever spells of passing found McAleny on the edge of the box, with the former Everton man curling past Archer to double the lead.
With little else to report in an otherwise uneventful first-half, The Lions headed in at the half-time break with a uphill struggle in front of them in the remaining 45 minutes.
McAleny looked for the hat-trick as the second-half began, but his effort was captured by Archer at the second attempt after an initial parry.
Jed Wallace tried his luck with 52 minutes on the clock, but skewed his shot wide of Simon Eastwood's post.
Lee Gregory set Aiden O'Brien clean through on goal on the hour-mark, but the striker's tame effort was saved by Eastwood. Seconds later, Johnson forced Archer into a save at the other end and Oxford looked to put the game to bed.
With 71 minutes on the clock, The U's trebled their lead, as Ruffels headed home a corner-kick.
MSC Player of the Year Steve Morison attempted to get The Lions back into the game on 74 minutes, but his effort was curled wide. Nine minutes later, the striker got his head to substitute Shane Ferguson's cross, but glanced wide.
There were further half-chances late on, but The Lions succumbed to a first home defeat since December.
Millwall: Archer, Craig (Ferguson, 46'), Williams, Thompson, Gregory, Romeo, Wallace, Webster, Morison, O'Brien (Worrall, 78'), Cooper. Subs not used: King, Cummings, Martin, Onyedinma, Butcher.
Oxford United: Eastwood, Ribeiro, Skarz, Lundstram, Nelson, Maguire (Hemmings, 85'), McAleny, Ruffels, Raglan, Johnson (Hall, 85'), Carroll (Rothwell, 78'). Subs not used: Stevens, Edwards, Long, Dunkley.
Scorers: McAleny (6', 9'), Ruffels (71')
Referee: Dean Whitestone
Attendance: 12,533 (630)