Gylfi Sigurdsson’s first Premier League goal for Everton proved scant consolation as the Blues slipped to a 4-1 defeat on the south coast.
After Dusan Tadic had slotted Southampton into an 18th-minute lead, Sigurdsson levelled matters on the stroke of half-time with a 20-yard beauty, picking the ball up outside the area and unleashing a curled finish which hit the underside of the bar and bobbled over the line.
But two headed goals from Charlie Austin after the break put the hosts in control, before Steven Davis wrapped up the Saints' win with a neat finish three minutes from time.
Caretaker boss David Unsworth called for a positive reaction from his Blues players following the defeat to Atalanta in the Europa League on Thursday night.
“We are looking for performance levels we have had recently in the league,” said Unsworth, who made eight changes to the team that faced the Italians, with just Michael Keane, Jonjoe Kenny and Kevin Mirallas keeping their places in the starting XI.
“Against Watford and Crystal Palace – and in the second half at Leicester - this group of players were fantastic. They played with spirit and desire and put points on the board.
“We are looking for a reaction, albeit it’s a different team from the other night.”
The first chance of the game fell to the Saints when Virgil Van Dijk nodded a corner into the path of Austin, who was in space 10 yards out, but the striker blazed over the bar.
Everton then hit back with a chance of their own when Aaron Lennon and Dominic Calvert-Lewin carved out an opening for Mirallas but the Belgian dragged his shot wide from the edge of the area.
Southampton were beginning to look menacing down the flanks, with full-backs Cedric Soares and Ryan Bertrand looking to bomb forwards on the overlap at every opportunity.
Soares served up another golden opportunity in the 11th minute when he out-muscled Sigurdsson on the touchline, before crossing towards the near post, where Austin was lurking with intent. The striker’s volley looked destined for the bottom corner but instead it struck the post and bounced to safety.
In contrast, Everton were struggling to make any in-roads as an attacking force, apart from a half chance for Mirallas, who pounced on a mix-up in the Saints’ defence, but his touch let him down at the vital moment.
Within seconds of that opportunity going begging, another devastating counter-attack from the home side led to the opening goal.
A swift raid down the left eventually led to Bertrand crossing for Tadic, who shrugged off Leighton Baines in the centre, before deftly rolling the ball past the on-rushing Jordan Pickford.
The Blues had barely recovered from that blow when they were swiftly dealt another one; Baines picking up an injury which brought his afternoon to a premature end.
That prompted a tactical reshuffle, with Ashley Williams coming into a back three as Unsworth switched to a 5-3-2 formation.
However, the Saints continued to dominate and Van Dijk nearly added a second when he rose to meet a corner but his header flashed wide of the far post.
With half-time approaching, the Blues then stunned the home fans into silence with a breathtaking equaliser.
Calvert-Lewin laid the ball off to Sigurdsson on the right-hand side of the box and the Icelandic international promptly wrong-footed two defenders, before bending a sublime shot over Fraser Foster. The ball struck the bar and post and then bounced off the bar again before crossing the line. It was a stunning goal.
That leveller gave the visitors a huge lift going into the interval - but any hopes of an away win evaporated within the first 14 minutes of the second half.
Southampton restored their lead in the 52nd minute when Bertrand crossed from the left and Austin made a darting run across the near post to guide a glancing header past Pickford via the underside of the crossbar.
Then six minutes later, the former QPR striker doubled his tally with a carbon copy effort.
This time, Tadic provided the ball in from the left and Austin flicked another header past Pickford.
And Everton’s miserable afternoon was completed on 87 minutes when Davis picked up a pass on the edge of the area and glided a curled finish into the far corner.