The Blues have been held in their last two Premier League matches but the men from west London stretched their unbeaten run to 10 matches with a 1-0 win against MOL Vidi at Stamford Bridge on Thursday night.
Indeed, Chelsea are chalked up as 8/13 (1.62) favourites with William Hill to pick up all three points from their trip to Hampshire.
Mark Hughes' men have won just five points from their opening seven league matches this season and William Hill offer 9/2 (5.50) that the Saints win this weekend, while the same firm go 3/1 (4.0) that Chelsea are held to a third successive Premier League draw.
Danny Ings is the only man to have scored more than two goals for Southampton so far this season and the on-loan Liverpool man is expected to lead the line again.
Chelsea fielded a number of fringe players against Vidi in midweek, but Maurizio Sarri's side will be back to full strength with the likes of Eden Hazard, Jorginho and Antonio Rudiger all set for immediate recalls to the starting line-up.
Southampton scored twice in a draw against Brighton and Hove Albion last month, but that was only the third time in their last 14 home matches in the Premier League that the Saints have scored more than one goal.
Hughes' side looked toothless in their 2-0 defeat against Wolves last weekend and, although Ings was on target for Saints against a makeshift Everton team in the EFL Cup on Tuesday night, the Blues will surely fancy their chances of keeping their at bay.
William Hill's 13/10 (2.30) quote, then, for Chelsea to keep a clean sheet could prove popular with punters.
With Chelsea in confident mood and Southampton short of belief, better value may lie in backing Sarri's in-form outfit to win without conceding.
Backing the Blues to win to nil at 17/10 (2.70) with William Hill could provide punters with a path to profit ahead of Sunday's showdown at St Mary's.