Hughes retained three at the back, handing starts to Maya Yoshida, Jan Bednarek and Wesley Hoedt — Jannick Vestergaard dropped the bench in favour of the Dutchman, who has been prone to error of late.
Southampton, which has slumped to three consecutive Premier League defeat, has conceded eight goals in that stretch and returned none.
Ross Barkley, meanwhile, scored his first goal for the Blues whilst Eden Hazard and Alvaro Morata each tallied at a deflated St. Mary’s on Sunday.
Danny Ings failed to relieve the pressure off the Southampton defence, as he missed an opportunity to give the hosts a shock lead.
The forward, who has been on target four times this season, was unable to keep his close-range effort on target and fired over the bar.
Saints would be duly punished when Barkley then created the opening for Chelsea.
Barkley pressed the Saints midfield into an error, before slipping the ball into Hazard to make it 1-0.
A frustrated Southampton, which was booked six times, nearly grabbed an equaliser only for Ryan Bertrand to side-foot Pierre-Emile Hojbjerg’s cross wide of the back post.
Six minutes, however, later the lead was doubled as Olivier Giroud’s free-kick set up Willian to fire across goal for a simple tap in from Barkley.
Kepa Arrizabalaga was made to work for his clean sheet, with Nathan Redmond and Ings testing the goalkeeper in the closing stages.
But Morata sent Saints into the international break with an ever sour taste, making a 3-0 inside stoppage time.
Southampton: McCarthy, Hoedt, Bedarek (Romeu 45), Yoshida, Bertrand, Cedric, Hojbjerg, Lemina, Redmond, Gabbiadini (Long 78), Ings.
Unused subs: Gunn (GK), Vestergaard, Davis, Targett, Austin.
Bookings: Bertrand (45+2), Lemina (54), Cedric (59), Romeu (61), Hojbjerg (66), Ings (90)
Chelsea: Arrizabalaga, Azpilicueta, David Luiz, Rudiger, Alonso, Jorginho, Kante, Barkley (Kovacic 81), Willian (Pedro 75), Hazard, Giroud (Morata 68).
Unused subs: Caballero, Cahill, Zappacosta, Fabregas.
Goals: Hazard (30), Barkley (57), Morata (90+3).