A late Harry Kane goal rescued Spurs a 1-1 draw in the fourth round, and they will face either Millwall or Rochdale if they beat the lower-league side in the replay at Wembley.
United will surely pose a sterner test, with Jose Mourinho's men thumping Yeovil Town 4-0 in the cup, having squeezed past Burnley 1-0 at Turf Moor in their previous Premier League game.
Spurs have been handed a number of injury boosts ahead of their encounter with United, with as many as four players returning to contention.
Left-back Danny Rose has overcome a knee injury and could start, while Hugo Lloris is available after missing the encounters with both Southampton and Newport.
Christian Eriksen will also be part of the squad following his own absence, along with Erik Lamela.
Toby Alderweireld continues his rehabilitation and is not yet ready to play.
Spurs have no suspended players.
TOTTENHAM STARTING LINE-UP
Spurs have drawn each of their last two games, and the absence of Christian Eriksen has been keenly felt.
The Denmark international makes Spurs tick, and the side have missed a player who can unlock defences, so he is likely to return to the starting XI.
Hugo Lloris will surely start in goal now he's fit, while Danny Rose could also replace Ben Davies, who came on against Newport as a substitute.
It remains to be seen if Moussa Sissoko will start after Mauricio Pochettino labelled him one of the club's "most important players" last week.
The protracted signing of Lucas Moura from PSG, if it is confirmed on transfer deadline day, is unlikely to impact the XI.
MAN UTD TEAM NEWS
With Michael Carrick now back available following a heart issue and Daley Blind free to play again after an ankle knock, United have only a couple of injuries to contend with.
Eric Bailly remains unavailable after ankle surgery, while Zlatan Ibrahimovic is still attempting to recover from knee trouble following his ACL damage.
Alexis Sanchez is set to make his Premier League debut for United, after making his first start for the club against Yeovil.
TV CHANNEL & KICK OFF TIME
The match at Wembley kicks off at 20:00 GMT on Wednesday, with live coverage available in the UK on BT Sport 1.
BEST OPTA MATCH FACTS
Spurs have won two of their seven Premier League matches against Manchester United under Mauricio Pochettino (D1 L4), as many as they’d won across their previous 26 games against the Red Devils, spanning eight different managers (Glenn Hoddle, David Pleat, Jacques Santini, Martin Jol, Juande Ramos, Harry Redknapp, Andre Villas-Boas, Tim Sherwood).
No team are on a current longer unbeaten run in the Premier League than Manchester United (8).
Alexis Sanchez could make his Premier League debut for Man Utd in this game; he scored in Arsenal’s 2-0 win against Spurs in November, and could become the third player to score against them for two different clubs in the same Premier League season after Eric Cantona in 1992-93 and Benito Carbone in 1999-00.
Harry Kane has had a hand in four goals in his last four Premier League games against teams managed by Jose Mourinho (three goals, one assist).