Thomas Tuchel's side ended a frustrating week on a high note thanks to Werner's contribution to a dramatic finale at Stamford Bridge.
After successive 1-0 defeats against Manchester City and Juventus, the Blues were in danger of another disappointing result with just minutes remaining in rain-soaked west London.
Trevoh Chalobah's early opener for Chelsea had been cancelled out by a James Ward-Prowse penalty in the second half.
But Ward-Prowse was sent off for an ugly lunge on Jorginho and Chelsea took full advantage as Werner restored their lead with six minutes left before Ben Chilwell wrapped up the points.
Chelsea sit two points clear of second-placed Liverpool, with Jurgen Klopp's side able to regain pole position if they beat champions Manchester City on Sunday.
Failure to defeat a Southampton side still seeking their first league win this season would have raised serious questions about the European champions.
So it was a huge relief for Tuchel to get back on track heading into the international break as Chelsea put one of their rare blips of the German's reign behind them.
Frustrated by what he labelled a "strange display" against Juventus on Wednesday and an equally lacklustre loss to City last weekend, Tuchel made five changes in a bid to shake up his "tired" team.
Ruben Loftus-Cheek was handed his first league start for Chelsea since September 2020, while Jorginho, Kai Havertz and Marcos Alonso were among those dropped.
For a man who has hardly put a foot wrong since taking charge in January, Tuchel showed he had not lost his magic touch as three of the players he brought into the team combined for the ninth-minute opener.
Loftus-Cheek towered above the Southampton defence to flick Chilwell's corner to the far post, where Chalobah dived to head home from close range.
Loftus-Cheek rifled narrowly wide from 18 yards and Chilwell's close-range shot was repelled by Alex McCarthy before Romelu Lukaku was correctly denied by an offside flag after he slotted home.
Werner thought he had doubled Chelsea's lead just before halftime when he rose above two defenders to head in from Callum Hudson-Odoi's cross.
But, with both teams back in position to kick off, a late VAR intervention convinced referee Martin Atkinson to rule that Cesar Azpilicueta had clipped Kyle Walker-Peters' heel much earlier in the build-up to the goal.
It was a debatable decision and Tuchel was incandescent with rage, waving his arms in protest as he briefly marched into the pitch – an incursion that earned a booking as boos cascaded down from the stands.
Shaken by that controversial moment, Chelsea lost their grip and Southampton took advantage to equalise in the 61st minute.
Teenage right-back Tino Livramento, who left Chelsea in the close-season, made an incisive raid that forced a panicked foul from Chilwell in the penalty area.
Atkinson pointed to the spot and Ward-Prowse stepped up to send Edouard Mendy the wrong way with the penalty.
But Ward-Prowse could have no complaints when Atkinson sent him off after consulting the pitchside monitor to review a nasty foul that left substitute Jorginho writhing in pain with 14 minutes left.
That proved the turning point as Chelsea took advantage of their numerical superiority in the 84th minute.
Ross Barkley sprayed a fine pass out to Azpilicueta and his half-volleyed cross was perfect for Werner to shoot low past McCarthy from close range.
Five minutes later, Lukaku and Azpilicueta hit the post in quick succession before Chilwell steered in the rebound.