Middlesbrough scored two goals in the dying seconds to earn a draw.
New Saints boss Harry Redknapp looked set to start his reign with a win when Kevin Phillips and Peter Crouch headed goals either side of the interval.
Phillips turned home Graeme Le Saux's cross after 44 minutes and Crouch repeated the feat after 63 minutes.
But Danny Higginbotham's own goal gave Middlesbrough hope after 89 minutes and Stewart Downing scored a spectacular equaliser from 20 yards in injury time.
Redknapp received a warm reception from the crowd who used to regard him as the enemy - and his side responded with a hugely positive performance.
Phillips was Southampton's main danger in the first half, stabbing narrowly wide then firing off target when well-placed.
Mark Viduka could have given Middlesbrough the lead when Southampton goalkeeper Antti Niemi could only push out Jimmy Floyd Hasselbaink's shot.
The ball fell just behind the Australian striker and his finish was tame.
Southampton broke the deadlock seconds before half-time with a beautifully worked goal.
Le Saux rolled back the years with a run down the left, then supplied a perfect cross for Phillips to power a header past Mark Schwarzer at the near post.
Middlesbrough were struggling to make an impact, but manager Steve McClaren almost got instant rewards with a substitution on the hour.
He sent on Szilard Nemeth for Tony McMahon, and the striker set up Downing, who was denied brilliantly by Niemi from only six yards.
It was a pivotal moment, with Saints doubling their advantage after 63 minutes.
Le Saux was the provider again, with a corner that Crouch headed past Schwarzer, who got his hands on the ball and should have kept the effort out.
Middlesbrough were becoming increasingly desperate, but they were unfortunate when a fierce drive from Hasselbaink struck the woodwork after 74 minutes.
Higginbotham then headed Downing's corner into his own net to give Middlesbrough hope after 89 minutes.
And the unlikeliest of comebacks was complete in injury time when the dangerous Downing flashed a stunning 20-yard into Niemi's bottom corner.
Southampton: Niemi, Nilsson, Lundekvam, Jakobsson,
Higginbotham, Fernandes (Telfer 45), Delap, Anders Svensson,
Le Saux, Phillips, Crouch.
Subs Not Used: Dodd, Smith, Griffit, Ormerod.
Goals: Phillips 45, Crouch 64.
Middlesbrough: Schwarzer, McMahon (Nemeth 60), Cooper,
Southgate, Reiziger, Parlour (Job 83), Boateng, Zenden,
Downing, Viduka, Hasselbaink.
Subs Not Used: Nash, Doriva, Davies.
Goals: Higginbotham 89 og, Downing 90.
Ref: N Barry (N Lincolnshire).