Phil Jagielka sits out Everton’s first home game of the new season after being shown a red card against Wolves last weekend.
The skipper is joined on the sidelines by long-term absentee James McCarthy (broken leg).
However, summer signings Bernard and Kurt Zouma – who played under Southampton boss Mark Hughes last season while on loan at Stoke City – could feature after training for the first time this week.
Andre Gomes and Yerry Mina miss out with minor hamstring and foot injuries respectively, while Cuco Martina has made a loan move to Stoke City.
For the Saints, Mohamed Elyounoussi may not be risked after tweaking a hamstring in training.
The Norwegian was one of four new faces in the Southampton ranks who made their debuts in the Saints’ 0-0 draw with Burnley last weekend. Fellow summer buys Jannik Vestergaard, Danny Ings and Stuart Armstrong (below) have all come in to boost Hughes’ options.
Armstrong, signed from Celtic, limped off against the Clarets but has recovered in time for the trip to Merseyside.
Stats, Facts and Milestones
This will be the Blues' 99th meeting with Southampton in all competitions.
A win against Southampton would be the 1,900th victory in Everton’s league history.
The Blues have an impressive home record against Southampton – they have not lost in their past 13 home meetings with the south coast side, with a record of W9 D4 L0, all in the Premier League. In the past 19, again all in the Premier League, the record is W13 D5 L1. Indeed, Everton have lost just twice in the last 35 meetings.
Seamus Coleman could make his 200th Premier League start for Everton. Should he do so, he will be the 13th player to reach that milestone for the Club. It will also be his 220th for the Blues in the league, which would take him alongside Joseph Yobo as joint 61st on Everton’s all-time league appearances chart and joint 12th in the Blues’ Premier League list.
Could Kurt Zouma be in line for his Everton debut? If so, he’ll become the first player with a surname beginning with ‘Z’ to play for the Toffees. That would leave just the letter ‘Q’ as the only letter remaining.
Everton have lost just once – to Tottenham Hotspur in September 2017 – in their last 17 Premier League games played on a Saturday with a 3pm kick-off.
One To Watch: Jannick Vestergaard
The towering defender was a summer signing from German side Borussia Mönchengladbach, having impressed in the Bundesliga for them, Werder Bremen and Hoffenheim.
He comes from a footballing family - his German grandfather Hannes Schröers and uncle Jan Schröers were footballers for Fortuna Dusseldorf and Bayer 05 Uerdingen respectively, while cousin Mika Schröers plays for Mönchengladbach's youth team.
Former Southampton defender Danny Higginbotham believes the Denmark international could turn out to be a key signing by Saints boss Hughes.
“Vestergaard has got big shoes to fill after Virgil Van Dijk’s departure last season but then again, he is 6’ 7” so I think he’ll be alright!” he tells Saturday’s matchday programme. “With the three at the back we saw against Burnley on the opening day, there is going to be a big onus on him.
“But you look at that team at Turf Moor at it was a good side. It’s got knowhow, it’s got a strong defence and it has pace going forward. Vestergaard is one of a number of good players Hughes has brought in and hopefully that bodes well for them this season because it’s a great football club.”
Man in the Middle: Lee Mason
A Premier League referee since 2006, Lee Mason oversaw 18 top flight games last season, dishing out 44 yellow cards and a pair of reds.
The 46-year-old, who hails from Portsmouth, last officiated an Everton fixture when taking charge of the Blues’ 1-1 draw at Swansea back in April.
His previous trip to Goodison Park was a September 2016 win over Middlesbrough, as Gareth Barry, Seamus Coleman and Romelu Lukaku all struck in the first half to seal a 3-1 victory.