With Arsenal, who are one point above them ahead of their match with Newcastle United, not playing until Monday, three points for the Toffees will help them apply pressure on their only realistic competitor for a top-four finish.
Roberto Martinez's side responded well to a surprise table-topping home defeat to Crystal Palace to comfortably beat Manchester United 2-0 last weekend and put the final nail in the coffin of former boss David Moyes.
Southampton's bright start to the season prompted premature notions that they could also be challenging for Europe, but they have steadily tailed away since closing November within two points of second place.
A run of only one win in their last five matches has seen these hopes completely evaporated, but the Saints can still look back on their first full campaign under Mauricio Pochettino as a definite success.
Top-flight consolidation and the continued abundance of talent emerging from its much-celebrated youth system gives Southampton plenty of reasons to smile ahead of what could be a difficult summer.
Jay Rodriguez was another garnering appreciative glances prior to sustaining cruciate knee ligament damage, an injury which will keep him out of the rest of the season and England's World Cup campaign.
The Saints have failed to score since his loss, but in Rickie Lambert, one of only four men in the division to reach double figures for both goals and assists this season, they can still trouble Everton's defence.
With goalkeeper Artur Boruc fully fit again after a back problem, Pochettino could name the same side that drew 0-0 with Aston Villa, with Victor Wanyama and James Ward-Prowse getting the nod in midfield.
The visitors will be forced into at least two alterations, with the ever-consistent Sylvain Distin joining Phil Jagielka on the defensive injury list with a potentially campaign-ending hamstring strain.
Martinez was adamant this week that Jagielka would not be rushed back from his two-month layoff to compensate for Distin's absence, and therefore Antolin Alcaraz will partner John Stones at centre-back.
Possible starting lineups
Southampton: Boruc; Clyne, Fonte, Lovren; Shaw; Wanyama, Schneiderlin; Lallana, Davis, Ward-Prowse; Lambert
Everton: Howard; Coleman, Stones, Alcaraz, Baines; McCarthy, Barry; Deulofeu, Osman, Naismith; Lukaku
Sports Mole says: 1-2