Pressure on Jose Mourinho had intensified after four games without a win in all competitions, although the club had dismissed reports he would be sacked regardless of Saturday's result.
It looked as though the manager's days could be numbered when Newcastle raced into a two-goal lead inside 10 minutes, but second-half goals from Juan Mata, Anthony Martial and substitute Sanchez sealed all three points in remarkable fashion.
Newcastle went in front for the first time in a league game this season only seven minutes in, as Kenedy ran onto Ayoze Perez's throughball, turned away from Ashley Young and curled past David de Gea.
It was 2-0 just three minutes later, Yoshinori Muto spinning beyond Young and firing home from 12 yards out, prompting Mourinho to bring on Mata for Eric Bailly in a drastic reshuffle of his side.
Marcus Rashford then headed a golden chance wide as sections of the United fans began to turn their ire towards the club's board, chanting in support of Mourinho and former captain Gary Neville, who criticised the club's hierarchy on Friday.
It could have been even worse for United before the break, with De Gea clawing away a header from Muto and Young perhaps lucky not to concede a penalty for blocking a free-kick with his arm – although Muto was likewise fortunate for escaping the same offence in his own box.
Mourinho jogged down the tunnel at half-time to considerable applause from the home fans, who should have been celebrating a goal five minutes after the restart, when Nemanja Matic blazed over the bar with the goal gaping after Martin Dubravka denied Paul Pogba.
Mata grabbed a lifeline 21 minutes from time with an excellent free-kick from 20 yards out, which seemed to spark some life back into the home side, and Martial made it 2-2 after combining brilliantly with Pogba before firing into the bottom-left corner.
United's pressure did not relent and Sanchez responded to his own critics with a fine header from Young's deep cross from the right, prompting resounding chants in support of Mourinho from the buoyant home crowd.
What it means: Pressure off Mourinho... for now
If the first half was one of United's worst of the season, their second was undoubtedly up there with their best.
The result lifts them only into eighth place in the table, but the impact it could have on Mourinho's future could be hugely important.
Newcastle battled hard for their first win of the season, but their defensive frailties were exposed and their inability to make the most of some half-chances punished.
Mourinho inspires United at last
Given the widespread claims of players falling out with the manager at Old Trafford, this was a result that owed everything to Mourinho's decisions.
Two of his substitutes, Mata and Sanchez, got on the scoresheet and the bold decision to reshape the team with Pogba as a deep-lying playmaker left Newcastle with no answer.
It was a performance of genuine heart, and one that reminded us Mourinho still has something to give.
Bailly's 19 minutes of ignominy
Bailly had not earned a start in the league since the 3-2 loss to Brighton and Hove Albion in August, and he could be facing a long wait for his next one given his display here.
The centre-back watched Kenedy run past him for Newcastle's first goal and generally looked all at sea until Mourinho substituted him in the 19th minute in order to bring on Mata.
Key Opta stats:
- Newcastle have lost eight Premier League matches when scoring first against Manchester United – a joint-high in the competition alongside Southampton v Man Utd and Sunderland v Chelsea (eight defeats).
- This is Newcastle’s worst-ever start to a top-flight season after eight games in terms of points (2 - 3pts for a win).
- Yoshinori Muto is the sixth Japanese player to score in the Premier League (after Junichi Inamoto, Hidetoshi Nakata, Shinji Kagawa, Maya Yoshida and Shinji Okazaki).
- Since his Premier League debut in August 2011, Manchester United’s Juan Mata has scored more direct free-kick goals in the Premier League than any other player (8).
- Paul Pogba has had a hand in 29 Premier League goals under Jose Mourinho at Manchester United (13 goals, 16 assists), more than any other player.
- Since 2016/17, Manchester United attacker Alexis Sanchez has scored three 90+ minute winners in the Premier League, more than any other player.
Should Mourinho remain in charge after the international break, his next match will be a trip to former club Chelsea. Juventus then visit Old Trafford three days later.
Newcastle will look to get over this result at home to Brighton on October 20.