Goals from Kenedy and Yoshi Muto inside the opening 10 minutes handed the Toon a 2-0 advantage at the break as United's poorest start to a top flight campaign for 29 years took another turn for the worse.
Reports prior to the game that Mourinho would be offloaded regardless of the result did not appear to galvanise the United team as they produced a desperate display in the opening 45 minutes.
Newcastle had not taken the lead in a game all season but inside just seven minutes they hit the front as Kenedy turned Ashley Young inside out and tucked the ball into the corner.
Just three minutes later United succumbed again as Muto turned Young and fired beyond David de Gea, to net his maiden goal for the Magpies.
After just 19 minutes Mourinho hauled off Eric Bailly, with Juan Mata coming on as Scott McTominay was moved into the centre of a misshapen United back-four.
Muto and captain Jamaal Lascelles spurned opportunities to extend the lead, while Newcastle should have been awarded a penalty when Young handled Jonjo Shelvey's free-kick.
United had a golden chance to get one back but Marcus Rashford nodded an excellent Romelu Lukaku cross wide.
Rafael Benitez's side had six attempts on goal in the first period, the most of any visiting side in the opening 45 minutes of a Premier League game at Old Trafford for 13 years.
Following a chorus of boos as the half-time whistle sounded, as Mourinho headed towards the tunnel a swell of support came from the crowd who chanted 'attack, attack, attack' - a suggestion they had not yet given up on the United boss.
The Red Devils sprung to life in the second half, however, with goals from Mata, Anthony Martial and Alexis Sanchez completing the comeback and sparing Mourinho's blushes in a 3-2 victory.
Whether the reports that Mourinho will be sacked regardless of the result remain to be seen, though the Old Trafford board would certainly have to think twice after such a dramatic comeback.