Sean Neave's penalty fired the young Magpies ahead at Heritage Park before Ben Parkinson, introduced from the bench at the restart, doubled United's lead within the opening two minutes of the second half.
United's youngsters were able to record a well-deserved clean sheet as Diarmuid O'Carroll's side enhanced their hopes of qualification for the Premier League 2 play-offs at the end of the season.
Newcastle's second-string began the Tyne-Tees derby in positive fashion as Jay Turner-Cooke went close to netting a third goal in his last five Premier League 2 matches. After Neave blocked Nathan Fisher's kick, the ball fell into Turner-Cooke's path but the South Shields-born midfielder's first-time effort from distance was directed wide of the right-hand post.
Neave, a representative of England at under-18 level, looked to have fired the Magpies ahead as Garang Kuol's initial shot from Leo Shahar's cross was parried into Neave's path by Fisher but the goal was disallowed after the Winlaton-born forward was adjudged to have strayed into an offside position.
Neave, however, managed to get his name on the scoresheet in the 26th minute after scoring from the penalty spot. The promising 17-year-old, who was named on the bench for United's Emirates FA Cup fourth round tie against Birmingham City last month, was tripped inside the box before confidently dispatched the resulting spot-kick into the bottom left-hand corner via the post.
Turner-Cooke, who spent the first half of the 2023/24 campaign on loan at Scottish Premiership side St Johnstone, almost doubled the visitors' lead shortly but his fierce deflected strike from the edge of the box was held by Fisher.
Newcastle were fortunate to remain on level terms as Rio Patterson-Powell's teasing cross into the penalty area found Charlie Lennon at the back post but the Boro winger directed his close-range effort wide of the target
Garang Kuol, who represented Australia at the 2022 World Cup finals in Qatar, missed a glorious opportunity to extend United's lead further on the stroke of half-time as the 20-year-old forward, who joined United from Central Coast Mariners in January 2023, raced onto Scott Bailey's excellent through ball but could only place a low effort inches wide of the right-hand post.
Parkinson, returning to action after suffering a foot injury, netted his 12th goal of the season at under-21 level in the 47th minute. After Neave cleverly flicked the ball into Alfie Harrison's path, the Keighley-born youngster directed the ball into the substitute's path, who calmly placed the ball into the bottom left-hand corner.
Magpies goalkeeper Aidan Harris, another returning from injury, preserved United's hopes of a clean sheet as the 18-year-old shot-stopper, named on the bench for United's UEFA Champions League draw away at AC Milan, held Lennon's shot from the edge of the box after a dangerous run from the Boro forward.
Kuol went close to extending Newcastle's advantage in the closing stages as the Cairo-born youngster's curling effort from the edge of the box was clawed away by Fisher before being the highly-rated youngster was unable to net a sixth goal in his last nine competitive matches at under-21 level minutes later, as his low effort was pushed away by the Boro 'keeper.
Newcastle's youngsters are in cup action on Tuesday, 11th March when facing an away tie against Heaton Stannington at Grounsell Park in the Northumberland Senior Cup semi-finals (kick-off 7.30pm GMT) as they aim to book a final showdown with Morpeth Town at St. James' Park.
Newcastle United Under-21s: Aidan Harris, Leo Shahar (Rory Powell 59), Cathal Heffernan (c), Ciaran Thompson, Dylan Charlton, Rory Finneran, Scott Bailey (Ben Parkinson 46), Jay Turner-Cooke, Garang Kuol, Alfie Harrison (Ellis Stanton 72), Sean Neave (Darren Palmer 59).
Subs not used: Tyler Jones.