The Red Devils take on 2013 FA Cup winners Wigan of League One.
It is a must-win for Erik ten Hag as it will likely be Manchester United's only chance of silverware this season.
United have a very good record against Wigan, losing just one of their last 19 meetings.
But Wigan have been giant killings in the past, beating Manchester City in the final and again in 2018 when Pep Guardiola was in charge.
Defending champions Manchester City are the favourites to win the FA Cup this season, ahead of Liverpool and Chelsea.
Here are the odds via Grosvenor Sport:
Man City: 11/4
Liverpool: 5/1
Chelsea: 8/1
Tottenham: 8/1
Newcastle United: 10/1
Manchester United: 12/1
Aston Villa: 16/1
Brighton: 16/1
Fulham: 33/1
Bournemouth: 40/1
West Ham: 40/1
Wolves: 50/1
Brentford, Crystal Palace, Everton, Leeds, Leicester, Nottingham Forest: 66/1
Sheffield United: 80/1
Ipswich, Southampton, West Brom: 100/1
Luton: 125/1
Blackburn, Coventry, Norwich, Watford: 150/1
Birmingham, Sheffield Wednesday, Swansea: 200/1
Bolton, Charlton, Hull, Plymouth: 250/1
Wrexham: 400/1
Blackpool, Bristol Rovers: 500/1
Bristol City, Wigan: 1000/1
Patrick Bamford stole the headlines on Sunday for his terrific goal for Leeds in their 3-0 win over Peterborough.
The striker has struggled in front of goal this season but proved class is permanent with a rocket volley from distance.
Darts sensation Luke Littler believes his beloved Manchester United can go one better than last season and win the FA Cup.
He said ahead of the Wigan clash: "I think we need the mental strength to think that we can win this."
Twenty three teams have been confirmed for the fourth round, with a number of replays still to take place.
Here are the ball numbers for the draw:
The FA Cup fourth round draw gets underway on ITV at 7:50pm.
Maidstone United are the lowest ranked team left in the competition after the National League South side beat League One Stevenage on Saturday.
Four of the Big Six Premier League teams also progressed to the fourth round, with only Arsenal missing out following their defeat to Liverpool.
Manchester United travel to Wigan in an 8pm kick-off tonight looking to replicate last season's success where they reached the final.