Substitute Charlie Austin scored seven minutes into his Southampton debut to inflict more Old Trafford pain on a lacklustre Manchester United.
Austin rose to head home a corner in the 87th minute to win an otherwise dour game of few chances.
Southampton have now won at United in the league for the last two seasons.
United and their manager Louis van Gaal were booed off by home fans at full-time after producing just one shot on target in 90 minutes.
They have won just one of their past five home games - and have failed to score in three of those.
United's first-half record in front of goal is even worse. They have now gone eight hours and 26 minutes without scoring in the first 45 minutes of games at Old Trafford.
Van Gaal's side are now five points behind fourth-placed Tottenham, who won 3-1 at Crystal Palace on Saturday.
Southampton are now just four points and three league places behind United, having won their past three matches. The win also ends a four-match losing streak away from St Mary's for Ronald Koeman's team.