A first-half double from Christian Stuani ensured David Moyes' home debut as Sunderland boss ended in a 2-1 Wear-Tees derby defeat.
Sunderland's threadbare and injury ravaged squad remain without a Premier League point after back-to-back defeats in the opening two games.
Sunderland - who lost captain John O'Shea to injury in the first half - started well but were left stunned when Stuani fired Boro in front after just 13 minutes with a stunning strike.
He added a second on the stroke of half-time, with Moyes's side leaving the field to loud boos around the Stadium of Light.
The Black Cats rallied after the break but couldn't build on Patrick van Aanholt's 71st strike, with new signings a must over the coming days.
The sides last met in the Premier League in 2009.
Moyes kept faith with youth, with Duncan Watmore and Lynden Gooch again favoured over the more experienced Jeremain Lens and Wahbi Khazri - who were both on the bench.
As expected, Fabio Borini missed out with a toe injury so there were first starts for Manchester United loanee Adnan Januzaj and £8million summer signing Papy Djilobodji.
Djilobodji made his full debut alongside captain John O'Shea after Younes Kaboul's £3.5million departure to Watford.
Everton-target Lamine Kone, who this week turned down a new contract offer, was not in the squad after complaining of a back injury less than 24-hours after rejecting the new deal.
Januzaj started brightly down the right-hand side, beating George Friend in the opening few minutes before seeing his cross go straight into the hands of Brad Guzan.
Hardworking Sunderland had started well, with Boro shaky at the back and unable to keep hold of the ball.
Januzaj was probing and always looking for the ball, with Sunderland pressing Boro high up the pitch.
Aitor Karanka's side had barely had a kick but took the lead 13 minutes in through Christian Stuani's stunning strike from outside the area.
He wasn't closed down by van Aanholt and picked his spot from 25-yards, the ball flying into the top left-hand corner of Vito Mannone's goal.
It could soon have been 2-0 to the visitors, Stewart Downing's delicate pass to Gaston Ramirez just overhit as the Boro forward bore down on goal.
The pace of the game slowed after Boro's shock goal, with Ramirez seeing an effort deflect off Djilobodji into the hands of Mannone.
Januzaj had the measure of Friend all first half, but he couldn't make the most of his breaks into the box, with his crossing misplaced.
Jack Rodwell then blasted over from 25-yards out 28 minutes in.
Sunderland's afternoon then went from bad to worse after captain O'Shea was forced off with what appeared to be a muscle injury.
New signing Steven Pienaar was on in his place, with Rodwell dropping back into central defence.
Moyes home debut then turned into a nightmare when Boro doubled their lead on the stroke of half-time.
Adam Forshaw won the ball, moved inside and played in Negredo, who was played onside by van Aanholt.
He then turned Rodwell before rolling the ball across for Stuani to smash home.
Boos accompanied the half-time whistle as Moyes and his stunned Sunderland players made their way down the tunnel.
Half-time: Sunderland 0 Middlesbrough 2
Paddy McNair was taken off at the break, with Jeremain Lens on in his place, playing behind Defoe with Gooch in a deeper role in front of the back four.
Boro, who boasted the strongest defensive record in the Championship last season, were proving difficult to break down, with Sunderland again dominating the possession.
Defoe had a penalty appealed turned down after a clumsy foul by Antonio Barragan, as the hosts piled on the pressure.
Januzaj fluffed his shot after excellent work from Lens to play him in, before van Aanholt forced a superb, low save from Brad Guzan in the Boro goal - the first time he'd been tested.
Lens had a stronger appeal for a penalty turned down - Barragan again involved - before the Dutchman then saw his effort deflected wide for another Sunderland corner.
Ben Gibson then produced a great block, not that he knew much about it, 65 minutes in to deny Defoe from close range.
It was all Sunderland but resilient Boro were holding firm.
The Teessiders still looked dangerous on the break though, with Mannone having to be sharp to close down Negredo who was bearing down on him.
Sunderland finally got the goal their endeavour deserved, Defoe laying the ball off to Watmore who saw his low shot palmed back into the danger area by Guzan.
Van Aanholt rushed onto the loose ball like a train, 71 minutes in, to half the deficit.
Moments later, Sunderland were almost level, Guzan spilling Januzaj's attempt before getting up to block Love's rebounded effort.
Moyes turned to 17-year-old Joel Asoro from the subs bench for the final 10 minutes, with Watmore taken off after running himself into the ground.
Asoro the club's youngest ever Premier League player, at just 17 years and 117 days old.
But Sunderland couldn't regain any momentum in the final stages, with Boro seeing out the game comfortably to leave Moyes pointless after the opening two games.
Full-time: Sunderland 1 Middlesbrough 2
Sunderland AFC (4-2-3-1): Mannone, van Aanholt, Djilobodji, O’Shea (C) (Pienaar, 37), McNair (Lens, 45), Love, Rodwell, Gooch, Watmore (Asoro, 80), Januzaj, Defoe.
Subs Not Used: Pickford, Khazri, T Robson, J Robson.
Booked: Gooch (80)
Goals: Van Aanholt (71)
Middlesbrough FC (4-2-3-1): Guzan, Nsue (Ayala, 82), Barragan, Gibson, Friend (C), Forshaw, Clayton, Stuani, Ramirez (Adomah, 59), Downing, Negredo (Nugent, 90).
Subs Not Used: Dimi, Baptiste, De Sart, Fischer.
Booked: Clayton (25)
Goals: Stuani (13, 45)
Referee: Martin Atkinson (Bradford)