The contest will be the third time the two sides have met already this calendar year, after Southampton won in the Premier League on New Year's Day and the teams played out a 1-1 draw at St Mary's in the initial cup fixture.
Here, Sports Mole looks at how Jose Mourinho could set his side up for the contest, with the winners facing a home game against Norwich City in the next round.
While Mourinho will not go as far as his old adversaries Liverpool when it comes to giving first-team players a night off for this replay, a number of changes are expected with the Premier League top-four race still the priority.
It is still likely to be a team full of first-team experience, though, and the options for rotation are limited at the top of the field anyway with Harry Kane still sidelined due to a hamstring injury.
Fernandes could make just his second start since his January arrival, having also been named in the XI at St Mary's, but fellow new signing Steven Bergwijn is ineligible due to FA rules dictating that a player must have been able to play in the initial game if they are to feature in a replay.
Other players who have been on the fringes of late, such as Erik Lamela, Tanguy Ndombele, Eric Dier and Ryan Sessegnon, will be hopeful of a start, while Paulo Gazzaniga could fill in for the fit-again Hugo Lloris in goal.
Jan Vertonghen is another who could come into the fold, and Mourinho could even consider a 3-4-3 formation in order to allow the likes of Sessegnon and Serge Aurier more attacking freedom down the wings.