This will be Sean Dyche's first trip to the Saints as Everton boss, but the two have already met this season, when Southampton knocked the Toffees out of the EFL Cup on penalties in September.
Match preview
For just the third time in Premier League history, a team has started a campaign with just one point from their opening 10 games, as Southampton join Sheffield United (2020-21 and 2023-24) as the only other club to make such a poor start.
Despite all their struggles in the league though, Russell Martin has led his side to the quarter-finals of the EFL Cup, with three wins in that competition, including a 3-2 success over Stoke City on Tuesday.
Criticism was incoming once again though despite progressing, as Martin's side squandered a 2-0 lead, and had 83% possession in the second half, but just one shot on target to show for it - James Bree's 25-yard winner in the final few minutes.
There are some promising signs for Southampton, but the philosophy of Martin is clearly hurting results on the field, even though Pep Guardiola waxed lyrical about the Saints following Manchester City's 1-0 win over them last week, like he does with every side that plays in a similar fashion to his style.
Prior to the narrow defeat at the Etihad, Southampton came very close to a maiden victory numerous times, conceding a 95th-minute equaliser to Ipswich Town, taking the lead away at Arsenal, and contriving to lose after going 2-0 up at home to Leicester City.
Persistent failure to get over the line means that the Saints are now 22 games without a Premier League win - only Derby County (32 games, 2007-08) and Sunderland (26 games, 2002-05) have gone on longer winless streaks in the competition.
Next up is Everton, and that could be a good omen for the struggling South Coast outfit, as they are the club they have beaten more often than any other in Premier League history with 13 victories.
The Toffees are notoriously poor travellers to this part of the country, as they have also encountered great difficulty when going to Bournemouth, but despite losing on seven of their previous 10 visits to St Mary's, they did win here the last time Southampton were a Premier League club.
In one of very few wins Frank Lampard achieved in his second season at the helm, Everton were 2-1 victors here in October 2022, and now have the opportunity to record back-to-back wins at this venue for the first time since 1992.
Having now gone five games unbeaten suggests that they are capable of doing so, especially after ending a 14-game winless run away from home in beating Ipswich Town 2-0 two weeks ago.
Everton's last defeat was on penalties to their upcoming opponents in the EFL Cup, as fortunes were quickly turned around following a morale-boosting win at home to Crystal Palace.
Ahead of facing another newly-promoted side, that win over the Tractor Boys means the Toffees are now six unbeaten against teams recently up from the Championship - winning four.
The following outing for Dyche's side saw them snatch a point at home to Fulham last Saturday, as substitute Beto dug Everton out of a hole after a very disappointing performance.
Everton are still down in 16th, but sitting on nine points gives them a healthy buffer to the relegation zone, and they are just three points off a spot in the top half, if they can sort out their poor goal difference.
Southampton Premier League form:
L
D
L
L
L
L
Southampton form (all competitions):
D
L
L
L
L
W
Everton Premier League form:
L
D
W
D
W
D
Everton form (all competitions):
L
D
W
D
W
D
Team News
After both being doubts for the cup tie with Stoke in midweek, Southampton's Yukinari Sugawara was fit enough to feature, and even though Flynn Downes was not, he should be fine to return here.
Young prodigy Tyler Dibling was subbed at half time at the Etihad last week, but Martin confirmed that was down to fatigue, and after resting the winger in midweek, he is also set to return to the starting XI.
Martin picked a relatively strong side for the cup win, with Kyle Walker-Peters the only other player who could return, as Will Smallbone and Ross Stewart remain sidelined with injury.
Jarrad Branthwaite was fit last week for Everton, but was surprisingly left on the bench as Dyche rewarded Michael Keane with another start after his performance against Ipswich.
While Branthwaite is likely to return, another of Everton's key performers could be missing, as Dwight McNeil limped off late on in the Fulham draw, and has not been present in training this week.
Beto's goalscoring impact off the bench is unlikely to see him promoted to the starting XI, as Dominic Calvert-Lewin will always be the man utilised by Dyche, despite him now going five games without a goal.
Armando Broja is still not ready to make his debut, while James Garner and Tim Iroegbunam are missing in midfield, but right-back pair Seamus Coleman and Nathan Patterson have returned since the last international break.
Southampton possible starting lineup:
Ramsdale; Sugawara, Harwood-Bellis, Bednarek, Manning, Walker-Peters; Dibling, Aribo, Downes, Mateus Fernandes; Archer
Everton possible starting lineup:
Pickford; Young, Tarkowski, Branthwaite, Mykolenko; Gueye, Doucoure; Harrison, Lindstrom, Ndiaye; Calvert-Lewin
We say: Southampton 1-2 Everton
Everton capitalised on a poor Ipswich performance to record their first win on the road since December in their last away outing, and facing another newly-promoted side struggling near the bottom should give them some confidence of moving further away from trouble.