The Saints, now under the tutelage of former Chelsea striker Mark Hughes, are battling desperately against relegation, and although added cup fixtures may be seen as a distraction by some, securing an unlikely appearance in the final would go a long way towards lifting spirits inside St. Mary's.
For Antonio Conte's men, the FA Cup represents their last hope of silverware this term, and a consolation prize as their dismal title defence appears destined to culminate with a place outside the Premier League's top four.
The two side will also be familiar with one another, having met on the South Coast just a week ago, with Chelsea overturning a 2-0 deficit in the final 20 minutes to snatch what would have been three valuable points from Southampton's grasp.
The hero of the Blues' comeback was French striker Olivier Giroud, who entered from the substitutes' bench to net a brace, his first Premier League goals in a Chelsea shirt since his £18million arrival from Arsenal on the last day of the January transfer window.
But the inspiration behind Chelsea's fightback, and the constant thorn in Southampton's side on the day, was Willian.
That's been the case for much of the season at Stamford Bridge, too. While star man Eden Hazard has struggled to find a level of consistency, the Brazilian winger has been the driving force of the Chelsea attack.
Willian is the Blues' leading creator, with his assist for Hazard against the Saints his seventh of the season, and he also ranks in the Premier League's top ten attackers for open-play key passes per 90 minutes (2.03), successful take-ons per 90 (3.25) and expected goals assisted per 90 (xA90, 0.29).
In the 3-2 win at St. Mary's, in addition to his assist, for which he skilfully made his way to the byline before whipping in a dangerous cross with his weaker left foot, he created a game-leading six scoring chances for his colleagues.
With his pace, directness and technical quality, the 29-year-old, who is set to be a starter for Brazil at this summer's World Cup, is quite a handful.
If Southampton are to hold out any hope of progressing to the final, they must find a way to shackle the former Shakhtar Donestk star, a feat much easier said than done.
Hughes elected to match Chelsea's 3-4-3 shape last week, using Ryan Bertrand and Cédric Soares in the wing-back positions. The success the Saints enjoyed in the opening 70 minutes might well have encouraged the former Stoke City and Blackburn Rovers boss to revisit this approach at Wembley.
By using two defensive-minded players in the wing-back positions, the outside centre-backs in the back three should, in theory, benefit from additional protection. But with Chelsea's own wing-backs bombing on, it will be difficult for the Saints to avoid allowing Willian to manufacture one-v-ne situations in the attacking third without further support from the central midfielders.
For this, former Chelsea destroyer Oriol Romeu could hold the key for Southampton. The Barcelona-schooled defensive midfielder has the discipline and tactical nous to know exactly when to fall back to aid his backline.
It might also be wise for Romeu to be granted permission to adjust his position depending on Willian's movement, as last week the Brazilian conjured his assist after switching from his berth on the right flank over to the left. To avoid potentially hazardous instances where responsibly must be passed between midfielders as the Chelsea attacker wanders, allowing the ex-Barça man to drift accordingly might be the most simple approach.
Such is Willian's ability and impressive form this season, Southampton need only allow their concentration to slip for one moment and the brilliant Brazilian could be booking Chelsea's place in the final.