Oxford striker Jon-Paul Pittman will miss the clash with Fleetwood and the next 12 weeks after having surgery.
The 26-year-old suffered a dislocated shoulder earlier this month but looked set for a January return to action before his shoulder popped out again, meaning he will have to go under the knife.
Manager Chris Wilder, who celebrated four years in charge of the U's on Friday, will also be without Adam Chapman, who fell awkwardly and injured his ankle in Tuesday's 2-0 FA Cup victory over Accrington.
Meanwhile, experienced defender Michael Duberry came through his late return to action against Accrington unscathed having not played since May.
But Simon Heslop is unavailable again as he serves the last game of his three-match ban.
Oxford are 18th in League Two ahead of their first-ever meeting with The Cod Army, eight points below the play-off places and eight above the relegation zone.
Fleetwood captain Steve McNulty is pushing for a start in Graham Alexander's side.
McNulty has not featured since suffering a calf injury during the 3-2 FA Cup defeat to Aldershot that cost Alexander's predecessor Micky Mellon his job at the start of this month.
The centre-back was named as an unused substitute for last weekend's 2-2 draw at Gillingham and he has played a full part in training this week.
Striker Jon Parkin will be absent once more with a hamstring injury, while veteran midfielder Barry Ferguson continues to be troubled by a groin complaint.
Having guided The Cod Army to consecutive draws, Alexander is looking for his first win as manager of a club who have not tasted victory for five matches in all competitions.