A goalless draw against champions Liverpool at Anfield on Sunday was enough to keep them at the summit and, while results elsewhere could knock them off before they are back in action, winning in West London would see them leading the way once again.
The Red Devils have now gone more than a year without losing a Premier League away game, and will be favourites to extend that streak against a Fulham side winless in the league since November.
Here, Sports Mole looks at how Ole Gunnar Solskjaer could line his side up for the contest.
Wednesday's match poses an interesting selection dilemma for Solskjaer, coming as it does just three days after one match against Liverpool in the league and four days before another in the cup.
The Premier League will be Man United's priority ahead of knocking their greatest rivals out of the FA Cup, but Solskjaer could still make changes nonetheless as he looks to keep his squad fresh.
While United's defence held firm an Anfield, the attack was underwhelming against a makeshift Liverpool backline and there could therefore be a minor shake-up for this game, with Mason Greenwood and Edinson Cavani both pushing for starts.
Marcus Rashford has scored on his last two Premier League trips to London - as many as he had on his first 19 such trips to the capital - and could become the first Man United player to score in three consecutive London games since the recently-retired Wayne Rooney in November 2014.
Luke Shaw was arguably Man United's standout performer against Liverpool but may be rested for the weekend with Alex Telles providing back-up, while Eric Bailly will also be hopeful of a recall after somewhat surprisingly missing out to the fit-again Victor Lindelof on Sunday.
Solskjaer may also bear in mind potential suspensions for his players; Harry Maguire, Bruno Fernandes and Shaw are all only one booking away from a ban, but the five-card threshold increases after this match and so the trio could be in line to sit out if Solskjaer opts for caution.
The United boss rubbished the idea of protecting Maguire against a card in a recent game against Burnley, though, so is not likely to let those concerns rule any of his players out.
Watch the Sports Mole Football Shorts prediction for this game below: