The North-East outfit, who last lifted the League Cup in 2004 under the management of Steve McClaren, will be looking to continue their solid form this season against the Red Devils.
Although Louis van Gaal has prioritised winning the Premier League, the Dutchman will be determined to secure his first piece of silverware of his tenure with the Red Devils.
As a result, the Red Devils have a point to prove in the competition to add to their four trophy wins in the tournament.
Van Gaal's men have been dogged by their inconsistent form over the course of the campaign, which has included impressive wins over Liverpool and Everton in recent weeks, but poor defeats against Arsenal and PSV Eindhoven.
The club's performance in the Manchester derby highlighted the fact that they are not quite firing on all cylinders, despite another heavy outlay on players over the summer, even though Anthony Martial has enjoyed an impressive start to his career at Old Trafford.
United's home form has been integral to them keeping touch with the Premier League pacesetters at the start of the campaign as they have only dropped points in their 0-0 draw against Newcastle United, while they brushed aside Ipswich Town with ease in the last round of the League Cup.
Defensively, the Red Devils have been solid at Old Trafford this season, conceding just two goals and keeping five clean sheets in all competitions. Van Gaal will be confident that if his side can produce another resilient outing they will be able to book their place in the fifth round.
Recent form: W
Recent form (all competitions): WWLWDD
Middlesbrough ended a three-match winless run in the Championship with a 3-1 comeback victory over Wolverhampton Wanderers on Saturday.
Aitor Karanka would have been concerned about his team's form when they fell behind to a first-half strike from David Edwards, but Boro rallied in the second half though goals from Diego Fabbrini, Grant Leadbitter and Stewart Downing to secure their first win of the month.
The North-East outfit had won six matches on the bounce before they lost to Reading at the start of the month, which started their poor run of results over the course of the month. However, Karanka's men have found their form just in time for their trip to Old Trafford.
Middlesbrough will travel to face the Red Devils with confidence following their victory over Manchester City last season in the FA Cup at the Etihad Stadium. The club will be determined to prove they can cope with the quality of United as they seek a return to the top flight.
The Spaniard's side coasted through to the fourth round with away victories over Oldham Athletic, Burton Albion and Wolverhampton Wanderers, with the goalscoring prowess of Christian Stuani crucial to their success so far in the competition as the Uruguayan has notched four goals.
Middlesbrough's record in the League Cup has been poor since they won the tournament in the 2003-04 campaign as they have only progressed beyond the fourth round once in the past 12 years.
Boro's form on the road has been patchy following their recent defeats to the Royals and Cardiff City, while their usually stoic defence has kept just one clean sheet in their past four matches. Karanka will know that his team will have to raise the level of their game against United.
Recent form: WWW
Recent form (all competitions): WWLDLW
Van Gaal could rest several of his first-team players in the match to give some of his squad players a chance of action against Boro.
Downing played through a knock against Wolves on Saturday and could come through the problem to play, while Adomah suffered a twisted ankle at Molineux. Stuani and Forshaw did not play at the weekend, and are unlikely to feature against United, but new loan signing Bruno Zuculini could make his debut.
Man Utd possible starting lineup:
Romero; Darmian, McNair, Smalling, Blind; Carrick, Schneiderlin, Fellaini; Lingard, Pereira, Wilson
Middlesbrough possible starting lineup:
Konstantopoulos; Kalas, Ayala, Gibson, Friend; Leadbitter, Clayton, Fabbrini; De Pena, Downing; Nugent
Head To Head
The teams last met in the 2008-09 campaign and the Red Devils won all three of the meetings over the course of the season, including in the League Cup.
Meanwhile, strikes from Cristiano Ronaldo, Nani and Giggs won the third-round League Cup match 3-1 at Old Trafford in their first clash of the season.
Over the course of history, United have dominated the fixture winning 62 of the matches, compared to Middlesbrough's 33, while 28 of the encounters have ended in draws.
We say: Man Utd 2-1 Middlesbrough
United have been strong at Old Trafford over the course of the season, and although Middlesbrough will provide a stern test, Van Gaal's men should have enough to see off the Championship side to advance to the next round of the competition.