Striker Graziano Pelle claimed his first Premier League goal in 15 matches to help lift Southampton up to fifth place in the table and add to Hull’s relegation worries.
Substitute James Ward-Prowse opened the scoring from the penalty spot after former Hull striker Shane Long had been fouled by Tigers defender Alex Bruce.
James Chester almost equalised but his header was cleared off the line.
Pelle then drove home his 13th goal of the season as Hull stayed in 17th spot.
Ronald Koeman’s side have now matched their Premier League record of 56 points which they achieved last season when finishing eighth under Maurico Pochettino.
They have won their last three home games, while Hull’s losing run now stretches to three matches and they remain only two points above the relegation places.
Hull face a tough run-in with games to come away to Crystal Palace, home to Liverpool, Arsenal and Burnley, away to Tottenham and then at home to Manchester United on the final day.
Southampton, also chasing a highest top-flight finish since they came fifth in 1985, have been short of goals in recent weeks with just five in their last nine games.
But a return to form for Pelle, whose last goal came in the FA Cup in January, was another bonus on a positive afternoon for the Saints, who rested England international Nathaniel Clyne.