Dennis Praet's first goal for the Football Club put the Foxes ahead on 14 minutes, but a deflected effort from Stuart Armstrong, before the break, and Danny Ings' late strike sealed the points.
Inside just six minutes, City No.1 Kasper Schmeichel was called upon to make an excellent double save to deny Ings after a stray pass from Barnes allowed the 27-year-old to run at goal.
Leicester recovered from that early scare and they lead after 14 minutes as Jamie Vardy, celebrating his 33rd birthday, broke down the left and crossed it low for Praet to convert from close range.
The Saints, though, were level inside five minutes. It came in fortuitous circumstances as Armstrong's shot took a heavy deflection off James Maddison, giving Schmeichel little chance to make the save.
Vardy had the ball in the net on the half-hour mark, after Ricardo Pereira's tackle ricocheted into his path. The flag was raised quickly, however, and VAR stepped in to confirm the assistant referee's call.
Before the interval, City's visitors from the South Coast twice went incredibly close to taking the lead as Ings rattled the crossbar on two occasions inside 60 seconds, but it remained 1-1 at the break.
At the other end, Alex McCarthy made a fantastic point-blank save from Jonny Evans' close-range header, but there was another scare in Leicester's penalty area in the 62nd penalty.
Referee Lee Mason pointed to the penalty spot when a challenge from Söyüncü brought Shane Long down in the 18-yard box. A VAR check, though, eventually ruled that the Irishman had strayed offside.
Second-half substitute Kelechi Iheanacho also had the ball in the net with a smart flicked finish before it was ruled out for offside but, with nine minutes remaining, Southampton took the lead.
Ings was free behind Leicester's backline and, while Schmeichel was able to get a knee onto his low shot, the former Liverpool striker's attempt had enough power to continue on its intended trajectory.
Schmeichel had to make an outstanding, one-handed save to stop Ings from adding another to his tally before, in Southampton's area, McCarthy rushed off his line to smother Iheanacho's effort.
With a minute of normal time to play, Evans did beat McCarthy with a glanced header from Maddison's free-kick. VAR, though, later ruled that the Northern Ireland defender had strayed offside.
Defender Jonny Evans briefly thought he had made it 2-2 in the latter moments.
Sixty seconds remained and Leicester thought they had rescued a precious point as Jonny Evans wheeled away in celebration after nodding it past Saints shot-stopper Alex McCarthy.
However, it was a short-lived moment of relief as VAR stepped in to rightly disallow the goal as Evans did appear to have strayed beyond Southampton's last man before James Maddison's cross.
Kasper Schmeichel was among the most impressive Foxes players on Saturday.
Matt Elliott said on LCFC Radio: "I thought Dennis Praet battled valiantly in midfield and got himself a goal, while James Maddison came into his own in the latter stages of the game as well.
"Leicester couldn't really capitalise on that. It's a reflection of how the game went, but I think Kasper Schmeichel made a great double-save and one or two others as well."
Where does it leave us?
Foxes manager Brendan Rodgers watches on from the sidelines at King Power Stadium.
The Foxes remain second in the Premier League on 44 points, ahead of third-placed Manchester City's visit to Aston Villa on Sunday, with Pep Guardiola's men a point adrift.
City are next in action in Lancashire against Sean Dyche's Burnley side in a week.
A trip to Burnley is next up for Leicester, who will be able to make use of a full week-long break in football, before heading to Turf Moor next Sunday (2pm GMT kick-off).
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