Southampton forward Che Adams came off the bench to inflict a potentially decisive blow to former club Sheffield United's slim hopes of avoiding relegation.
Adams, who began his professional career at Bramall Lane, secured his side's victory with a terrific strike at the start of the second half after captain James Ward-Prowse's had earlier scored a penalty.
It was Adams' first goal since December, against the same opponents, and ensured Ralph Hasenhuttl's side should be playing Premier League football next season after a first win in 10 matches.
For Chris Wilder's Blades however, the situation looks bleak 12 points from safety with only 10 games left.