The Blues produced their best performance and result of the season immediately prior to the international break, running out 4-0 winners over Crystal Palace to settle down a distinctly ordinary start.
However, they now face a Saints side that has won their last two games without conceding and that beat Chelsea at Stamford Bridge in the corresponding fixture last season.
Here, Sports Mole looks at how Frank Lampard could set his side up for the contest.
There has been mixed news on the injury front for Chelsea during the international break.
On the plus side, Hakim Ziyech is now fully fit and in contention to make his competitive debut for the Blues on Saturday, having overcome a knee injury.
Christian Pulisic is also now ready for a starting role, leaving Lampard with an embarrassment of riches up front with Timo Werner, Kai Havertz, Mason Mount, Callum Hudson-Odoi, Tammy Abraham and Olivier Giroud all competing for places too.
However, while Ziyech and Pulisic are set to make their long-awaited returns, Chelsea have also been hit by the news that Edouard Mendy and N'Golo Kante picked up injuries for their respective countries.
Mendy has been ruled out while Kante is set for a late fitness test, but Lampard is unlikely to take any unnecessary risks with a muscle injury and the Frenchman could therefore miss out this weekend.
That would likely result in a return to the starting lineup for Mateo Kovacic and under-fire keeper Kepa Arrizabalaga, the latter of whom may have a chance to stake his claim for the gloves again sooner than expected.
Thiago Silva has also been ruled out having only recently returned from his travels with Brazil, but Ben Chilwell is available despite being forced to pull out of the England squad.
Antonio Rudiger may therefore be hopeful of a first appearance of the season after his deadline day move away never materialised, although the fact that Andreas Christensen is closer to full fitness may give him the edge.
Jorginho will be hopeful of holding on to his position even if Kante is passed fit having scored three goals in three games this season - already only one short of his tally for the entire 2019-20 campaign.
Werner could return to centre-forward given the competition for places in the wide areas, which would see Abraham and Giroud battling to make an impact off the bench.
Giroud's past record against Southampton may give him the edge in that particular battle; the Frenchman has directly contributed to five goals in his last four league games against the Saints and has netted seven times against them in total - the last four of which have all come as a sub.
Watch the Sports Mole Football Shorts prediction for this game below: