Jose Mourinho’s men, who are now six points clear with a game in hand on City, took the lead through Diego Costa on 11 minutes but a Dusan Tadic penalty eight minutes later levelled the game.
Plenty of chances were created and wasted by Chelsea with Southampton goalkeeper Fraser Forster in splendid form in the second half, repelling a Loic Remy effort away from goal in the dying minutes from which John Terry wasted the rebound.
Diego Costa also hit a post for the hosts, who will have been frustrated not to have been awarded two penalties when Branislav Ivanovic was clipped in the first-half by Tadic and Costa went down under pressure from Jose Fonte.
Chelsea started at a high tempo, pressuring the Southampton back four whenever possible and they opened the scoring on 11 minutes.
Costa hadn’t found the net in the Premier League since grabbing Chelsea’s third goal in the 5-0 drubbing of Swansea in January but was on hand to power home an Ivanovic cross from eight yards with a thumping header.
However, much like against PSG on Wednesday, Chelsea took their foot off the gas after taking the lead and had Thibaut Courtois to thank just one minute later as he denied Sadio Mane from close range.
Undeterred by that missed chance, Mane came again at the Chelsea backline and won a penalty with his next attacking run.
The Senegal international drove at the heart of the hosts’ defence and only a lunging tackle from behind by Nemanja Matic could halt his progress.
The Chelsea man, who was booked, got a foot on the ball but took the man first and Tadic duly dispatched the penalty, although Courtois did get a foot to the ball.
Ivanovic then wanted a penalty of his own minutes later when he went down after Tadic had stood on the back of his heel, but referee Mike Dean was unmoved.
Chelsea’s goalkeeper continued to be kept busier than Mourinho would have liked as he palmed away a firm Tadic drive from the edge of the box on 29 minutes before Shane Long’s continued pace in behind John Terry created a chance for Mane, who forced Courtois into another stop from the edge of area.
Matic could have been sent off early in the second period after hauling down Mane 30 yards out but survived a second booking. Mourinho then withdrew the midfielder from the action, putting on Ramires in his place, and from then on Chelsea took charge of the game.
Costa should have doubled his tally for the afternoon on 53 minutes but he diverted a Willian cross onto the post from just three yards out.
Always at the heart of the game, Costa then had a penalty appeal waved away which was nearly identical to the one that was awarded to Southampton in first half as Fonte made a lunging tackle from behind as the Chelsea man ran deep into the penalty area.
Forster then came to the fore in the final 25 minutes to repel wave after wave of Chelsea attacks.
The England goalkeeper made a brilliant double stop to first deny Cesc Fabregas from eight yards and then was up quickly to divert Eden Hazard’s rebound away from danger.
Oscar then tried his luck from 12 yards after a brilliant Fabregas pass but Forster made himself big and thwarted that effort before a Cesar Azpilicueta shot from the edge of the area was turned around the post by the Saints stopper.
Chelsea saved their best chance until last though.
Substitute Remy found himself in space eight yards from goal but his shot was blocked away by Forster.
The ball rebounded to Terry, who smacked an effort goal-bound which was cleared off the line by James Ward-Prowse. After a couple of ricochets the ball broke back to Terry eight yards out but he fired a shot wide of the far post when it looked easier to score.
Chelsea: Courtois (7); Ivanovic (6), Cahill (6), Terry (6), Azpilicueta (6); Matic (6), Fabregas (6); Willian (6), Oscar (6), Hazard (7); Diego Costa (7)
Subs: Ramires (7), Remy (6), Cuadrado (5)
Southampton: Forster (7), Clyne (6), Fonte (7), Alderweireld (7), Bertrand (7), Wanyama (7), Schneiderlin (7), S. Davis (6), Tadi? (6), Mané (7), Long (6)
Subs: Pelle (6), Ward-Prowse (6), Djuricic (6)
Man of the Match: Fraser Forster