Own goals from Antolin Alcaraz and Seamus Coleman cost Roberto Martinez's side as it failed to keep the pressure on Arsenal in the race to claim a Champions League place.
The Merseysiders came into Saturday's game at St. Mary's Stadium looking for a win to take them above Arsenal and into fourth, with Arsene Wenger's side not playing until Monday. However, a nightmare start saw them fall behind inside a minute as Antolin Alcaraz's spectacular error put the hosts ahead.
Having benefited from three own goals themselves in recent weeks, the visitors were their own worst enemies and fell further behind after the half-hour as Seamus Coleman scored into his net.
Southampton is now six points clear of Newcastle United — Arsenal's next opponent — and remains on course to equal its highest Premier League finish of eighth.
Everton remains a point behind Arsenal and Roberto Martinez looks as though he may have to wait another year at least to achieve his aim of taking the club into the UEFA Champions League.
Martinez's side could hardly have made a worse start to the game. It coughed up possession from kickoff and the ball eventually found Rickie Lambert, whose inswinging cross from the left was headed past Tim Howard by a flying Alcaraz.
A lack of cutting edge in attack hampered Everton and it almost conceded again 20 minutes in as Steven Davis shot wide from 12 yards after another swift break down the right flank.
Coleman's attacking instincts were giving Southampton space, but a rare foray down the opposite side of the pitch led to the hosts' second.
Nathaniel Clyne zipped up the wing and clipped in a deep cross that John Stones failed to clear, giving Coleman no time to readjust, the ball bouncing off his forehead and into the net.
Romelu Lukaku headed over from 4 yards as Everton sought a way back into the contest, but the Toffees were fortunate not to concede a penalty as Stones appeared to handle Adam Lallana's cross.
Martinez introduced Leon Osman and Aiden McGeady in an attempt to spark life into his attack, but Lambert came close to a Southampton third as his 59th-minute free kick nicked the outside of Howard's left-hand post.
McGeady's trickery on the left presented Lukaku with another glorious chance to score, but he planted a header straight at Artur Boruc.
Everton's challenge largely fizzled out as Southampton dominated the ball, consigning the Merseyside club to its fifth successive winless trip to St. Mary's.
Having cost former boss David Moyes his job at Manchester United by extinguishing its hopes of reaching the Champions League last week, Everton's own bid now looks in serious jeopardy.