Stamford Bridge was silenced in the first minute of Sunday's clash when Jay Rodriguez punished an error from Michael Essien - making his first Premier League start since May 2012 - to put Saints ahead.
But second-half goals from Gary Cahill, John Terry and substitute Demba Ba produced an emphatic turnaround and kept the Blues on the Gunners' heels.
Jose Mourinho made four changes to his side, with midfielders Juan Mata and Essien, striker Fernando Torres and forward Eden Hazard all starting. John Obi Mikel, Frank Lampard, Willian and the injured Samuel Eto'o were the players who made way following the 1-0 UEFA Champions League defeat at Basel in midweek.
Saints showed two changes from the side which began last weekend's loss at Arsenal, with Dejan Lovren and Dani Osvaldo replacing Jos Hooiveld and Rickie Lambert.
The visitors took the lead after just 13 seconds as Essien's woeful attempted backpass went straight over the head of Cahill to Rodriguez 16 yards out and he tucked the ball past Petr Cech.
Essien's afternoon got worse when he was booked for diving just before the half-hour mark, and he was subsequently hauled off at half-time and replaced by Ba. Lampard came on for Oscar shortly before the break.
One of the last acts of the first half saw Hazard and Mata combine well to get in a cross which was met by a header from Torres that Artur Boruc kept out with a brilliant one-handed save going to his right, before the ball was hacked clear.
However, Chelsea did bring themselves level 10 minutes after the restart. Mata's corner was met by Branislav Ivanovic who headed goalwards and although Ba redirected the ball onto the post, it broke again to Cahill who headed in his first goal of 2013 from close range.
Boruc had to depart the action soon afterwards due to a finger injury, meaning Paulo Gazzaniga was summoned from the bench.
And the 21-year-old Argentinian goalkeeper was picking the ball out of his net just four minutes after his introduction. Mata's corner was headed out to Lampard on the edge of the box and he volleyed a pass back out to the Spaniard. His cross was met by a glancing header from Terry which found the top corner to mark his 400th Premier League appearance in style.
Chelsea were still well below their best despite squeezing Southampton into submission. Ba did well to meet Cesar Azpilicueta's lofted pass behind Jose Fonte, but dragged his shot wide with the goal gaping.
Torres was replaced by Mikel for the final few minutes as Mourinho sought further defensive security.
And Chelsea's comeback was capped in the 90th minute as Ramires got in a left-wing cross that was met first time by Ba as he slid in and the ball found the corner of the net.
The result keeps Mourinho's men second in the table after 13 games played, four points behind Arsenal and two above third-placed Manchester City. Saints end the weekend in seventh spot.
Chelsea's assignments next week are at Sunderland and then Stoke, while Southampton host Aston Villa on Wednesday night before taking on City at St Mary's on Saturday.