United were looking to bounce back from successive home defeats by Tottenham Hotspur, in the league, and Swansea City, in the FA Cup, but instead they lost again, and to the Premier League's bottom side.
Ryan Giggs, who had earlier hit the crossbar, gifted Sunderland the lead with an own goal and despite Nemanja Vidic equalising early in the second half, Fabio Borini's
65th-minute penalty gave the hosts victory.
Having eliminated Chelsea in the previous round, Sunderland remain on course to reach a first domestic cup final since 1992, when they lost to Liverpool in the FA Cup final.
For United manager David Moyes, however, the gloom grows ever darker, with his hopes of claiming a piece of major domestic silverware in his maiden season severely compromised ahead of the second leg on January 22.
The importance of the fixture was evident in the fact that both managers made seven changes to the sides they fielded in the FA Cup at the weekend, although United were once again without the injured Wayne Rooney.
Eager to exploit any uncertainty in the visiting ranks, Sunderland looked to get balls into the box at the earliest opportunity and saw Borini drag an early shot wide from just outside the area.
However, emboldened by the purposeful running of Adnan Januzaj, United began to assert control of the game.
Giggs sent a deflected 25-yard shot against the crossbar, while Januzaj had a goal ruled out for offside and Vidic planted a header wide from a corner shortly before half-time. Sunderland emerged unscathed, though, and in first-half stoppage time they exploited defensive inattention from United to go ahead.
From Sebastian Larsson's deep free-kick, Wes Brown stole in behind Michael Carrick to volley the ball back across goal, and in attempting to prevent Phil Bardsley from prodding home, Giggs succeeded only in scoring himself.
The timing of the goal felt like a sucker-punch, but Manchester United regrouped at the interval and equalised within seven minutes of kick-off in the second period.
Tom Cleverley curled a left-wing corner to the back post and Vidic outjumped former team-mates Brown and John O'Shea to power a header past Vito Mannone.
For the umpteenth time this season, however, Manchester United's momentum was to desert them.
Jonny Evans had to hobble off with an injury, and after Borini had sliced wide and Larsson had drawn a sharp save from visiting goalkeeper David de Gea, Sunderland restored their lead.
Cleverley was adjudged to have impeded Adam Johnson as he tore into the penalty area and after referee Andre Marriner pointed to the spot, Borini calmly lifted the ball past De Gea from 12 yards.
Scorer of a brace on his previous visit to the Stadium of Light, Januzaj carried the fight to Sunderland again, shooting narrowly off target on three occasions, but even their new boy wonder could not rescue United.