Oliver McBurnie thought he’d put the Blades in front shortly after half-time, converting from close range after a free-kick from Oliver Norwood, only for VAR to rule John Egan had attempted to play the ball from an offside positon before McBurnie scored.
Midway through the second half, Moussa Djenepo added insult to injury when he fired Saints in front, with Sheffield United again frustrated when a VAR review failed to award them a penalty later in the contest.
The home side applied intense pressure in the closing stages but Southampton held on gainfully, securing back-to-back away wins in the Premier League for the first time since March 2017, with the home side’s afternoon of misery completed late on when Billy Sharp was sent off.
Both sides had early chances. Che Adams cannoned the woodwork with a powerful shot before Saints countered at pace and David McGoldrick tested Angus Gunn.
After the half-hour mark, the home side were left head in hands when McGoldrick got on the end of Norwood’s brilliant free-kick, only to see Sofiane Boufal clear the danger with a last-gasp intervention.
At the other end, Boufal could have opened the scoring right on the break, but his weak shot was easily saved by Dean Henderson.
Early in the second half, United had their moment with VAR although to their credit they remained on the front foot and made life tough for Southampton.
Midway through the second half, Djenepo made the difference. He showed excellent composure under fierce pressure inside the box, evading a number of challenges before rifling into the bottom corner.
With 15 minutes remaining, referee Lee Mason was surrounded by Blades players claiming a penalty for handball but a VAR review failed to get the desired outcome.
Sheffield United still had the wind in their sails looking for a leveller but were undone when Sharp’s crude challenge on Oriol Romeu brought him a straight red card with four minutes left.