Antonio Conte opted to shuffle his pack at Wembley Stadium, with two of his star performers handed a well-earned rest.
Both made it onto the field against Tottenham, with Hazard providing the spark to seal a 4-2 victory, but they should feel fresher than most in a midweek fixture.
Cesc Fabregas and Gary Cahill also come back into the starting XI, with Nathan Ake, Pedro, Willian and Michy Batshuayi dropping out.
The Blues head into the game looking to stretch their lead at the top of the Premier League table to seven points, with Spurs not in action until Wednesday.
Chelsea team: Courtois; Azpilicueta, David Luiz, Cahill (c); Moses, Kante, Matic, Alonso; Fabregas, Diego Costa, Hazard. Subs: Begovic, Ake, Terry, Chalobah, Willian, Pedro, Batshuayi.
Southampton team: Forster, Cedric, Stephens, Yoshida, Bertrand, Romeu, Davis (c), Ward-Prowse, Tadic, Boufal, Gabbiadini. Subs: Hassen, Caceres, Clasie, Hojbjerg, Long, Redmond, Rodriguez.