United have had a mixed start to life under interim manager Ralf Rangnick, with the German manager losing only one of his first ten games in charge - but the quality of performance has been well below standards expected at Old Trafford.
However, this Middlesbrough will by no means be an automatic bye to the Fifth Round - they are fighting for the play-offs under Chris Wilder, who notably caused United some issues when he was in charge at Sheffield United.
Manchester United are unlikely to have too many injury doubts going into this clash, with the only real concern being whether Luke Shaw will be fit enough to return from his recent hamstring injury.
Aaron Wan-Bissaka had a spell of illness before United's mini-winter break but could be in contention to return to the squad here.
Returning from international competition is Eric Bailly, but his involvement against Middlesbrough is doubtful, as is the selection of Fred and Alex Telles, who returned late in the week from Brazil duty.
For the visitors, it could be a full debut for Arsenal loanee Folarin Balogun after his January move to the north east.
James Lea Siliki is still on AFCON duty with Cameroon and will not be available, though new signing Riley McGree is set for a debut after his move from Birmingham during the window.
Manchester United: Henderson; Wan-Bissaka, Lindelof, Maguire, Dalot; Matic, McTominay, Fernandes; Sancho, Rashford, Elanga
Middlesbrough: Lumley; McNair, Bamba, Fry; Jones, McGree, Crookes, Tavernier, Taylor; Sporar, Balogun
Ones to watch
United's most exciting player as it stands is arguably young Swede Anthony Elanga, whose performances over the last few weeks have impressed coaches and supporters alike.
The attacker was initially a member of Ole Gunnar Solskjaer's first-team plans this term, and his replacement Rangnick has also taken to the academy graduate as he offers something different on the wing, tending to find space behind the defence and take on his man rather than looking for a simpler pass.
A perfect fit for Ralf Rangnick's high-energy system ⚡— Sky Sports Premier League (@SkySportsPL) February 2, 2022
For the visitors, arguably their most creative player is Marcus Tavernier, the brother of Rangers captain James.
The winger creates the most chances for Boro, fashioning 39 opportunities for team-mates at an average of 1.44 per match.
United's struggling midfield will have to find a way to get a foothold on the numbers in Middlesbrough's counterpart, especially with the creativity of Tavernier.
The last time the two sides met was at the Riverside Stadium in 2017 - when Boro were last in the Premier League.
Marouane Fellaini and Jesse Lingard gave United a two-goal lead at the Riverside, before Rudy Gestede pulled one back ten minutes from time to seed some doubt into the visitors.
However, Antonio Valencia's stoppage time effort, capitalising on a mistake from ex-United keeper Victor Valdes, ensured the Reds would walk away with all three points.
Where to watch
For UK viewers, the match is set to be shown on terrestrial television, as ITV will be broadcasting from Old Trafford. Coverage for the clash begins at 19:30 BST.
The match can also be streamed on the ITV Hub.