Currently five points adrift of the top four, the Blues are struggling to qualify for next year's Champions League.
However, they are 4/9 (1.44) favourites with bet365 to give their fans something to cheer about by taking their place in a second consecutive FA Cup final.
Meanwhile, Mark Hughes' team face a huge fight to avoid relegation to the Championship, but can be backed at 6/1 (7.00) to pull off a morale-boosting upset in this clash.
None of the last six encounters between this pair have resulted in draws, but you can get odds of 10/3 (4.33) on them taking this one into extra-time after a deadlocked 90 minutes.
Danny Drinkwater, David Luiz and Ethan Ampadu are all ruled out through injury, while Marcos Alonso is suspended.
Jack Stephens will serve the last game of his three-match suspension for a red card against Arsenal, with Mario Lemina injured and Sofiane Boufal a doubt due to illness.
The Saints thought they were on the verge of a crucial victory when they were leading 2-0 after an hour in last weekend’s league encounter against this opposition.
However, they were left empty-handed after conceding three times in the space of just eight minutes – the fourth consecutive match against top flight opposition in which they had conceded three goals.
Although they did keep a clean sheet away to Leicester on Thursday, it is hard to see the Southampton backline holding strong against an attack that has scored 12 goals in the last five encounters between the teams.
With Antonio Conte’s side having failed to keep a clean sheet in 10 successive fixtures themselves, odds of 19/20 (1.95) seem generous on both teams finding the net