Having rattled the crossbar in the first half, Matty Longstaff - partnering his older brother Sean in midfield - fizzed in the winner with a superb 72nd-minute strike at St James' Park.
Things would have been different had Harry Maguire converted a simple chance before the break, while Fabian Schar denied Marcus Rashford a tap-in just prior to Newcastle's goal.
But it was 19-year-old Matty Longstaff who had the final say as Steve Bruce, on his 400th Premier League game as a manager, secured a first win over the Red Devils, whose winless run on the road has stretched to 11 matches in all competitions.
A TRUE GEORDIE— NBC Sports Soccer (@NBCSportsSoccer) October 6, 2019
NEWCASTLE LEAD pic.twitter.com/BaTAoEc6e1
Matty Longstaff sparked the match into life in the 28th minute, rattling the crossbar with a dipping long-range effort.
Sean Longstaff turned provider with a fantastic pass for Miguel Almiron soon after, only for the Paraguayan to hesitate when one-on-one with David De Gea - Maguire charging back to make a vital block.
Maguire should have made Newcastle pay for Almiron's profligacy but failed to direct a free header on target from six yards out.
Almiron wasted no chance in getting his next shot off, though failed to direct his effort anywhere near the target after latching onto Allan Saint-Maximin's pass.
Bruce introduced Andy Carroll with over half-an-hour to play and the change almost paid dividends when he connected with Matty Longstaff's cross, but turned his header over.
Schar made a vital intervention to prevent Rashford tucking home Daniel James' cross and Newcastle swiftly made his good work count.
Saint-Maximin led the charge, with Jetro Willems, who had been played onside by Andreas Pereira, supplying the cut-back for Matty Longstaff to hammer home his first goal and secure a vital win to lift Newcastle out of the bottom three.
What does it mean? Solskjaer in deep trouble
United's worst start to a Premier League season was confirmed with Monday's draw to Arsenal and the season seems to be quickly spiralling out of control for Solskjaer, whose side have the small matter of facing Liverpool to come after the international break.
The Red Devils sit 12th on nine points, their lowest points tally after eight games since 1989-90, while Newcastle's win has seen them leapfrog Everton and Southampton into 16th.
17 - Since Ole Gunnar Solskjaer was appointed permanently on March 28th, Manchester United have won just 17 points in 16 @premierleague matches (W4 D5 L7), the fourth-worst tally among the 17 ever-present teams in that time. Wheel. pic.twitter.com/cbd1OYGNv6— OptaJoe (@OptaJoe) October 6, 2019
Longstaff arrives on the big stage
Sean Longstaff was heavily linked with United in the off season but, though he had a fine game in midfield, it was his younger brother Matty who grabbed the headlines.
The teenager proved his strike in the first half was no fluke when he raced onto Willems' pass, sending a crisp, composed finish beyond De Gea to become the youngest player to score on their Premier League debut for Newcastle.
Rashford cuts a lonely figure
If one player epitomises United's struggles, it is Rashford. The England forward hardly had a chance throughout, with his only half-opportunity coming when Schar beat him to James' cross.
Shouldering the responsibility of carrying United's attack in the absence of Anthony Martial and Paul Pogba, Rashford – who started the season so well – seems to be crumbling under the pressure if recent performances are anything to go by.
Chelsea await Newcastle at Stamford Bridge after the international break, while United welcome league leaders and fierce rivals Liverpool to Old Trafford.