First-half action saw Saints head into the break with the narrow lead and they defended resolutely to hold on to all three points, denting the Blues' hopes of a top-four finishChelsea's top-four credentials are in doubt after they fell to a shock defeat to Southampton on Saturday, with Mauricio Pochettino's men dragging themselves towards safety.
Saints deservedly went ahead through Jay Rodriguez after a good start to the match, but were pulled back level when John Terry headed home. However a Rickie Lambert free-kick restored the hosts' lead before half-time and they held on for another top-half scalp after the break.
With a gruelling week ahead Rafa Benitez rested a number of key men for the clash, Eden Hazard, David Luiz and Ashley Cole all made way, while Juan Mata (illness) and Gary Cahill (knee) were unavailable. Therefore the likes of Ryan Bertrand, Terry, Marko Marin and Victor Moses started. Saints, meanwhile, were without injured Adam Lallana but young left back and reported Blues target Luke Shaw recovered in time.
The hosts started the brightest and had two decent chances to open the scoring through Rodriguez. The striker firstly drilled a half-volley over the bar after Lambert's header down, before breaking free of Terry with some inventive trickery only to roll the ball into Petr Cech's arms.
And Saints were rewarded for their continued pressure just after the 20-minute mark. Rodriguez received the ball from Lambert in a central position before moving it on to Steven Davis and making a darting run in behind the Chelsea defence. The Scot released it quickly and found the striker, leaving him to slot home past Cech.
Fernando Torres thought he had equalised just moments later when he had the ball in the net after breaking free of Jos Hooiveld, however he was penalised for handling in the build up and it was ruled out.
The Blues did get themselves back in the game, however, with just over half-an-hour played. Marin delivered a corner from the right flank which Terry headed home after losing his marker far too easily.
But the clash swayed back in the home side's favour just two minutes later when Bertrand was adjudged to have fouled Davis outside the Blues box. Saints captain Lambert stepped up and smashed the set-piece into the top-left corner of the goal, just out of Cech's reach.
Rodriguez called Cech into action once more with a powerful strike from distance but the score remained 2-1 as the half-time whistle was blown.
Clyne forced the Blues keeper into a low save at his near post just after the restart, before denying Marin with a fine challenge, but it was Chelsea who went closest to the next goal as half-time substitute keeper Kelvin Davis did magnificently well to tip over Moses' deflected effort.
Rodriguez then had two decent chances to give Saints some daylight, but was denied by a fine Cech save as he shot from a tight angle, before wasting the second opening with a heavy touch.
Benitez brought Hazard on as he searched for a vital goal and the Blues did indeed pile some pressure on the hosts, as well as having a penalty appeal turned down, but they just failed to find the cutting edge they needed in the final third.
Elsewhere James Ward-Prowse almost found Davis as Saints threatened on the counter-attack, before, down the other end, Hazard flashed a shot-cross just wide of the far post as the Blues' goal-mouth pressure continued.
Lampard failed to emulate Lambert as he flashed a late free-kick over the bar, with Saints able to hold on to a vital victory in their push for survival - also denting Chelsea's hopes of Champions League football next season.