Carlos Alcaraz gave Southampton the lead after 35 minutes, firing an effort past Leicester keeper Danny Ward.
Three minutes earlier, Ward had saved Saints captain James Ward-Prowse’s penalty after Timothy Castagne blocked a cross with his arm in the area.
Leicester’s Harry Souttar should have levelled the match in injury time but could only head the ball against the crossbar after Southampton keeper Gavin Bazunu was beaten by a James Maddison cross.
Southampton’s victory was just their second at home in the league this season and moved them off the foot of the table into 19th, one point behind 17th-placed Leeds and a position of safety.
Leicester could have gone as high as 12th with a win, but instead remain 15th, three points clear of the drop zone.
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Saints off bottom with rare home win
Southampton came into their fixture at St Mary’s off the back of a dismal loss to League Two Grimsby Town in the FA Cup fifth round on Wednesday and were aiming to avoid a club record sixth straight home defeat.
With supporters still reeling from Ward-Prowse’s penalty failure, Che Adams played through Alcaraz, who beat both the offside trap and Leicester keeper Ward with a driven shot into the bottom left corner.
It was the Argentine’s second goal for Southampton since joining from Racing Club in January and he received a standing ovation from the home fans when he limped off with a knock after 50 minutes.
Ruben Selles’ side held on for just a sixth league victory of the season, creating little in the second half as they dropped back and defended resolutely.
The result boosted their survival chances with the hosts hoping to become the first side to beat the drop having been bottom of the Premier League on 1 March since Leicester in 2015.
Pressure builds on wasteful Leicester
Since the Premier League resumed after the World Cup, Leicester have picked up just seven points from 10 matches.
Defeat at St Mary’s means they have now lost each of their past four, scoring once in a defeat by Championship side Blackburn Rovers in the FA Cup on Tuesday.
The visitors had the pick of the chances throughout with forward Kelechi Iheanacho heading three brilliant crosses off target in the first half.
Iheanacho was gifted an opportunity midway through the second period, intercepting a pass from Saints goalkeeper Gavin Bazunu, but the Nigerian’s lifted effort could only find the roof of the net.
And in the last embers of the match Bazunu failed to connect to Maddison’s outswinging cross, leaving Souttar with an open goal, but the defender’s header clipped the top of the crossbar and went over.
Southampton are away to Manchester United in their next match on Sunday, 12 March while Leicester are at home to Chelsea next Saturday.