It was a game in which United needed to win in order to reach the Play-Offs, however they relied on; Watford, Crystal Palace, Wolverhampton Wanderers and Ipswich Town to all slip up.
However at the bottom of the table a win for Southampton would surely allow the saints to retain their Championship status, only a result for Leicester City at Stoke City would prevent the Saints from beating the drop.
United battled had throughout the 90 minutes and there performance alone warranted all three points, but it wasn't to be - but when Jonathan Stead rounded the score at 2-2 on 65th minute the Blades looked well for the win.
But Stern John netted his second goal of the game four minutes later to produce a vital win and all three points before being sent off for a second book able offence.
3,200 Sheffield United made the long trip from South Yorkshire to Hamshire early in the morning, a 6:30am set off time for us meant an even early 4:00am wake up call. Despite the long day the fans travelled with a knowledge that a win and results elsewhere went their way then could end up in the Play-Offs.
And, for 20 minutes they were - 24 minutes in Billy Sharp found himself free on right hand side, he beat his marker before crossing for an unmarked Stephen Quinn whom had an easy task of heading the ball home, 1-0.
At the other end Paddy Kenny made great saves to keep the game in favour of the visitors, Inigo Idiakez been denied by the former Bury shot stopper before the Saints drew level three minutes before the break.
Jhon Viafara did enough to beat Derek Geary on the left hand side and his deflected cross (off Geary) flew straight onto the back post and to Marek Saganowski who headed home on the goal line.
In the second half Southampton came out all guns blazing and eight minutes in the Saints were out of the bottom three when Stern John slipped past Kenny after being put through by Saganowski - John was booked for his celebration.
United, still dreaming of making the Play-Offs threw on striking duo Luton Shelton and Jonathan Stead for Billy Sharp and Rob Hulse - and there tactical switch paid dividends when Shelton steered in from the left for Stead to finish stunningly at the near post on 65th minute, 2-2.
But four minutes later Trinidad & Tobago international forward John netted his 19th goal of the season when he turned his marker to slam the ball past Paddy Kenny.
And 15 minutes from time the Saints hero was handed his marching orders by referee Phil Joslin which he showed John a second yellow card of the game for a late challenge on defender Derek Geary.
United did all they could to find a way past Richard Wright in the Southampton goal but the Saints hung on and with Leicester City only being able to draw at Stoke City it meant the Foxes would be relegated to League One with the Saints retaining there Championship survival for at least another year.