Southampton clawed their way out of the Premiership's bottom three as Peter Crouch's double earned Saints their first away win of the season.
Andreas Jakobsson stabbed Saints ahead, only for Antti Niemi's error to gift Jimmy-Floyd Hasselbaink an equaliser.
Crouch restored Saints lead with a powerful header from Graeme Le Saux's pinpoint cross.
The lanky striker then deftly volleyed past Mark Schwarzer to dent Boro's hopes of a Uefa Cup spot finish.
Boro's bright start suggested they were not too jaded by their midweek exit from the Uefa Cup.
But Saints gradually wrestled control of midfield, largely through Nigel Quashie's prodigious work-rate.
Crouch planted an acrobatic bicycle kick over the bar, while it took a timely challenge from Franck Queudrue to deny the lanky striker after had been neatly picked out by Henri Camara.
Southampton rounded off a good spell of pressure by taking the lead on 15 minutes.
Boro failed to deal with a free-kick and, although Camara appeared to be offside when the ball was returned back in to the danger area, the Senegal striker kept a cool head to cross for Jakobsson to stab home at the far post.
Boro drew level after an error by the recalled Niemi.
The keeper tried to catch Boudewijn Zenden's powerful shot but only succeeded in spilling the ball for Joseph-Desire Job to set up Hasselbaink, who tapped home from close range.
Andreas Jakobsson celebrates firing Saints ahead
Boro had played with a hearty appetite for the game as they snapped into tackles to win possession.
They carved Southampton open for Szilard Nemeth to test Niemi, who parried the Slovakian striker's powerful shot to safety.
But Saints need for the points was greater and they nosed ahead again on the hour when Olivier Bernard produced the perfect cross for Crouch to climb above Gareth Southgate and head powerfully home.
Crouch was on fire and when Schwarzer failed to hold his piledriver, Camara was unable to convert the loose ball.
But Crouch gave Saints a two-goal cushion with a superbly deft finish, volleying Le Saux's cross past a flat-footed Schwarzer.
Niemi redeemed his first-half error with a stunning reaction save from Job's close-range shot.
That appeared to knock the stuffing out of the home team and there were few signs of a repeat of the late salvage act at St Mary's earlier in the season, when Boro scored twice in the last two minutes in Harry Redknapp's first game in charge of Saints.
Middlesbrough manager Steve McClaren:
"I accept fans' expectations are high but they're too quick to get on the players' backs.
"I can't fault the players' attitude, they gave everything against Southampton but in the end there was nothing left.
"We've got eight games left, we've got injured players coming back and we need everyone to stick together."
Southampton assistant manager Jim Smith:
"We had to win an away game, you can't go through the season without winning one and stay up.
"We go into a two-week international break with a huge psychological boost of being out of the bottom three.
"There's plenty of fight left in the bottom four, and Portsmouth and Fulham will be looking over their shoulders."
Middlesbrough: Schwarzer, Parnaby (Reiziger 68), Riggott, Southgate, Queudrue, Nemeth (Graham 68), Doriva, Zenden, Downing, Job, Hasselbaink.
Subs Not Used: Cooper, Wheater, Jones.
Goals: Hasselbaink 41.
Southampton: Niemi, Delap, Jakobsson, Lundekvam, Bernard, Telfer, Redknapp, Quashie, Le Saux (Anders Svensson 80), Camara (Phillips 69), Crouch.
Subs Not Used: Higginbotham, Davenport, Smith.
Goals: Jakobsson 14, Crouch 60, 67.
Referee: U Rennie (S Yorkshire).