The young Magpies took an early lead in the Group C clash at Meadow Park courtesy of Matheos Ferreira's strike before Farhaan Ali Wahid's composed effort drew the hosts level on the stroke of half-time.
Zak Brunt's second half header proved the difference as Newcastle's youngsters were edged out against Luke Garrard's cup holders, currently occupying top spot in the English fifth tier after an unbeaten start.
Robbie Stockdale made four changes from last week's Premier League 2 defeat against Fulham as 16-year-old goalkeeper Roman Dowell, who joined Newcastle's youth set-up at Under-9 level, was handed his competitive debut for United's second-string.
Teenage midfielder Sam Alabi, who signed his first professional contract with the Magpies in July, made his first U21s start since January while 17-year-old forward Michael Mills replaced Sean Neave in attack following the latter's season-long loan move to Wolverhampton Wanderers.
Newcastle got off to a bright start in Hertfordshire as Vakhtang Salia created the visitors' opening shot on target in the opening 40 seconds as the Georgian forward's long-range strike forced Boreham Wood goalkeeper Ted Curd into pushing the low drive out for a corner.
In the tenth minute, Ferreira fired Newcastle's youngsters into the lead as the Ashington-born winger raced onto Mason Miley's inviting pass in behind the Wood defence before firing a fierce effort towards Curd's front post.
Mills, a representative of England at Under-17 level, went close to doubling Newcastle's lead as the Manchester-born youngster showed great pace to evade his marker down the left flank but, after driving into the box, saw his effort pushed over the bar by Curd.
Dowell, who made his England U17s debut at the age of 15, produced a strong save to deny Ali Wahid as the left winger's powerful strike inside the box was turned away by the legs of the Boldon-born 'keeper.
Newcastle faced further attacking pressure from the Wood, with Jay Bird's volley inside the box flying wide of the right-hand post before Dowell palmed away a goal bound effort from Ali Wahid minutes later.
United's second-string, however, conceded in the 45th minute as Ali Wahid, on loan from Fulham, levelled for the National League outfit after exchanging a neat one-two with Regan Booty before calmly slotting the ball into the far right-hand corner.
Salia was unable to net his fourth goal of the 2026/27 season at Under-21 level shortly after the restart, collecting Mills' pass as the latter capitalised on Charlie O'Connell's initial slip but the Georgian's wild attempt from the edge of the box flew wide of the target.
The Goergia Under-21 international almost regained Newcastle's lead in terrific fashion shortly after as the 19-year-old intercepted Curd's loose pass before his audacious chip near the centre circle was tipped over the crossbar by the recovering Wood goalkeeper.
Johnny Emerson, who joined Newcastle's Academy in 2019, was introduced from the substitutes' bench to make his first competitive appearance at Under-21 level since April 2025 following a lengthy recovery from an anterior cruciate ligament (ACL) injury.
Newcastle, though, fell behind in the 72nd minute as Brunt, introduced from the bench, latched onto Ali Wahid's teasing cross into the box from the left flank before guiding a firm header into the left-hand corner.
Kyran Thompson, who signed his first professional contract with the Magpies last weekend, was introduced in the final stages, making his first outing for Newcastle at Under-21 level in the process, but the London-born forward was unable to salvage a point.
Newcastle United Under-21s: Roman Dowell, Henry Johnson, Dylan Charlton, Logan Watts, Miodrag Pivaš, Scott Bailey (c), Matheos Ferreira (Kacey Wooster 81), Mason Miley (Johnny Emerson 63), Vakhtang Salia (Afner Cá 63), Sam Alabi, Michael Mills (Kyran Thompson 73).
Subs not used: Luke Craggs, George Mair, Fraser Harper.
Photograph courtesy of Leonie Citron (Boreham Wood Football Club)
