The young Magpies, targeting a third successive league victory after wins against Blackburn Rovers and Aston Villa, fell behind in the first-half at the Magpies' Little Benton Academy through Sam Mather's volley before Ethan Ennis' solo finish doubled the visitors' lead in the final stages.
Diarmuid O'Carroll made three changes from the side which suffered a 3-1 defeat against Rotherham United in the EFL Trophy as Trevan Sanusi and Leo Shahar, who both represented England at under-18 level whilst on international duty, returned to the starting line-up in place of Ben Parkinson and Ciaran Thompson while Alfie Harrison, who joined the Magpies from Manchester City in February 2024, replaced Jay Turner-Cooke in the starting XI.
Sanusi, who made his Newcastle first-team debut during a pre-season friendly win against Hull City in July 2024, created the first attacking opportunity after combining with Magpies striker Josh Donaldson but the Birmingham-born winger was unable to beat Man United goalkeeper Dermot Mee to the ball, who collected in the process.
Magpies goalkeeper Aidan Harris, who made his under-21s debut as a 16-year-old, produced a key stop to deny Gabriele Biancheri after the Welsh striker's initial shot from Zach Baumann's cutback was saved by the teenage shot-stopper before the loose ball was importantly cleared by Newcastle midfielder Travis Hernes.
However, in the 16th minute, Newcastle fell behind as Mather latched onto Jayden Kamason's cross from the right flank before drilling a first-time effort past Harris.
Harrison, who made his first senior start during Newcastle's Sela Cup win against Stade Brestois at St. James' Park, went close to drawing the hosts level as the Keighley-born youngster's strike from the edge of the box was deflected wide by Man United skipper Louis Jackson.
In the second-half, Newcastle almost equalised through Anthony Munda as the Cowgate-born midfielder, who signed his first professional contract with his boyhood club last summer, exchanged passes with Hernes before the 18-year-old's strike at goal was heroically blocked by Finley McAllister.
Shahar, who joined Newcastle from hometown club Wolverhampton Wanderers in the summer of 2023, went close to netting his first goal at under-21 level, with the right-back latching onto a cleared ball before his vicious strike from the edge of the penalty area was blocked out for a corner by Tommy Rowe.
Jay Turner-Cooke, introduced from the bench after the hour mark, was unable to net his third goal in as many Premier League 2 matches as the attacking midfielder ran onto Sanusi's pass before drilling his attempt wide of the target.
In the 86th minute, Newcastle were dealt a tough blow as Ennis, ultimately, confirmed maximum points for the Red Devils, racing onto a lofted pass and, after evading a challenge in a crowded box, slotted a low effort into the bottom left-hand corner.
Newcastle United Under-21s: Aidan Harris, Leo Shahar, Cathal Heffernan (c), Charlie McArthur, Alex Murphy (Harry Powell 90), Travis Hernes, Anthony Munda, Alfie Harrison (Jay Turner-Cooke 65), Johnny Emerson (Ben Parkinson 65), Trevan Sanusi (James Huntley 77), Josh Donaldson.
Subs not used: Adam Harrison.
