Sir Alex Ferguson's Premier League giants travel to struggling Championship side Barnsley, while Blackburn also take on low-lying second-tier opposition in the form of Peterborough.
Elsewhere, there are all-top-flight clashes as Sunderland host Aston Villa, Portsmouth welcome Stoke, and Everton visit Tottenham in the quest to reach the quarter-finals.
Barnsley, conquerors of United in the 1998 FA Cup, welcome the defending Premier League champions to Oakwell for what promises to be an intriguing fixture in terms of sub-plot.
Ferguson, fresh from accepting a Football Association charge of improper conduct regarding his criticism of referee Alan Wiley, will inevitably shuffle his pack, but there are more interesting matters.
Barnsley manager Mark Robins famously saved the Scot's job when he was a United player by scoring a winning goal for the Red Devils in a 1990 FA Cup victory over Nottingham Forest.
Ferguson was expected to be sacked if United had lost to then cup specialists Forest, but the rest, as they say, is history.
Blackburn Rovers are also looking to avoid a shock when 21st-placed Championship outfit Peterborough arrive at Ewood Park, but they will have their work cut out.
Sam Allardyce's side were thrashed by Chelsea in the Premier League at the weekend and the club have been hit by swine flu, sparking reports that they could have requested for the clash with Posh to be postponed.
To make matters worse for Rovers, Peterborough manager Darren Ferguson, Sir Alex's son, saw his side record a morale-boosting 3-0 win over Scunthorpe on Saturday.
Sunderland would welcome a piece of silverware this season and Steve Bruce will have his side well motivated for their meeting with Villa at the Stadium of Light.
Bruce's return to Birmingham was spoilt at the weekend when the Black Cats lost at St Andrew's, while Villa were pegged back as they drew with Midlands rivals Wolves.
Portsmouth have suffered a wretched season so far and their priority is top-flight survival, and Stoke boss Tony Pulis has also said that he wants to stay in the Premier League.
It is therefore likely that Pulis and opposite number Paul Hart will make a number of changes to their first XIs when they cross swords at Fratton Park.
Tottenham, competition winners in 2008 and last season's defeated finalists, have a number of injury worries ahead of their fixture against Everton at White Hart Lane.
Out-of-favour striker Roman Pavlyuchenko is set to be offered the opportunity to impress by Harry Redknapp, who expects the Russia international to attract transfer interest in January.
Everton will want to bounce back from defeat at Bolton on Sunday and boss David Moyes may give fringe players the chance to demonstrate why they should replace first-team regulars, who have been threatened with the axe.