The Blues have only won three Premier League games in 2018 and Javier Hernandez's late equaliser at Stamford Bridge was a huge blow to their hopes of Champions League football.
Meanwhile, ex-Chelsea star Mark Hughes is now managing Southampton who have surprised many by finding themselves in the relegation zone with just six games left to play this season. This is the first of two games between the sides, with an FA Cup semi-final date pencilled in for the week after.
Thibaut Courtois returned to the starting lineup against West Ham, while Pedro came off the bench to return from what manager Antonio Conte described as a "physical problem."
Davide Zappacosta may return from a tendon issue, while David Luiz is likely to miss out with a recurrence of the knee injury that he suffered last season in a high challenge with Sergio Aguero.
Ethan Ampadu is out for the season with an ankle injury that he sustained in the UEFA Youth League match against Real Madrid, while Ross Barkley has been playing with the Under-23s as he bids for long-term fitness.
Chelsea have no players suspended or any at risk of getting a ban through an accumulation of yellow cards.
Chelsea potential starting line-up
Chelsea's match away to Southampton begins a busy week for the club, who have a rescheduled away trip to Burnley on Thursday before locking horns with the Saints again next Sunday.
Antonio Conte will have to rotate his squad as they aim to battle for pride in the league, while providing themselves with a platform to win the FA Cup.
Southampton will be playing for their lives in a match that is arguably more important to them than the FA Cup semi-final. Conte will therefore have to name a strong line up to face the south coast side, as he aims for only his second away win in 2018.
Southampton team news
Southampton will be without Jack Stephens after his reaction to Jack Wilshere's challenge on Sunday earned him a red card. Mario Lemina missed the game at the Emirates Stadium due to illness and may return to face Chelsea.
Shane Long picked up a knock against Arsenal and he is a minor doubt.
TV channel & kick-off time
The match takes place at 12:30 GMT on Saturday and it will be shown live in the UK on Sky Sports.
Best Opta match facts
Southampton have only won one of their nine Premier League games against Chelsea at St Mary’s Stadium (D2 L6), winning 2-1 in March 2013 thanks to goals from Jay Rodriguez and Rickie Lambert.
Chelsea have won their last four league games against Southampton – they’ve never won five in a row against them.
Mark Hughes has lost his last f our games against Chelsea as a manager (all with Stoke), with his side conceding 15 goals in that run.
If Southampton lose this game, Mark Hughes will become only the second manager to lose three Premier League games against the same opponent in a single season after Graeme Souness vs Arsenal in 2004-05.
Cesar Azpilicueta and Álvaro Morata have now combined for seven Premier League goals this season – in only one previous season have two Chelsea players combined for more (Frank Lampard and Didier Drogba in 2005-06, 8).