After a tight first-half, with Sean Neave hitting the post for the visitors, the Toon teenagers trailed on the stroke of half-time at the Ulrich-Haberland-Stadion, played outside of the BayArena, following Montrell Culbreath's glancing header.
Ferdinand Pohl's strike doubled Leverkusen's advantage shortly after the restart and despite Kyle Fitzgerald's impressive drive halving the deficit in the closing stages, the young Magpies were unable to grab a late equaliser as they left Germany empty-handed.
Adam Lawrence made six changes from the side which suffered a 2-0 defeat against Olympique de Marseille over a fortnight ago as Neave, who made his first team debut for Eddie Howe's side during a pre-season friendly against Celtic FC, returned from a one-match suspension while Sam Alabi, named on the bench for the Magpies' UEFA Champions League clas against Marseille, replaced the suspended Anthony Munda.
Isaac Moran, who joined the Magpies from Liverpool last summer, was handed his UEFA Youth League debut while Thomas Bryant, who celebrates his 19th birthday tomorrow, was handed his first competitive start in 362 days after recovering from a long-term injury.
The hosts created the opening goalscoring opportunity as Ivan Massek rose from Montrell Culbreath's dangerous cross from the right flank before heading over the crossbar.
Leverkusen had the ball in the net shortly after as Jeremiah Mensah's delivery into the box was deftly turned into the net by Culbreath but the goal was disallowed after the German teengaer had strayed into an offside position.
Seung-soo Park, who joined the Magpies from Suwon Bluewings last summer, went close to netting his first Magpies goal as the South Korean winger, a representative of his country at under-20 level, cut inside from the left flank before his low drive at goal was held by Leverkusen goalkeeper Jesper Schlich.
Newcastle were fortunate to remain on level terms as Culbreath's teasing delivery into the box found an umarked Emmanuel Owen but the stretching forward could only head the ball over the target.
After Bryant was stretchered off following a sliding challenge, Newcastle missed a glorious opportunity to break the deadlock through Joe Brayson as the 18-year-old striker rose from Dylan Charlton's inviting cross, the latter replacing Bryant from the bench minutes prior, but saw his glancing header fly wide of the right-hand post.
Magpies goalkeeper Roman Dowell, a representative of England at under-17 level, produced a key save to keep the visitors on level terms as Culbreath's cross-cum shot following a bursting run along the right wing was blocked by the promising youngster's left foot before the loose ball was eventually cleared to safety.
Newcastle went agonisingly close to taking the lead through Neave as the Winlaton-born forward hit the post, with the 18-year-old's drive from the edge of the box striking the foot of the left-hand post before Park headed over from Leo Shahar's bending cross.
Dowell produced an excellent save to deny Jeremiah Mensah as the Hebburn-born youngster, who celebrated his 16th birthday last week, stood tall to turn the Leverkusen forward's powerful effort out for a corner, who initially raced through on goal after beating Logan Watts to Sam Alabi's headed pass.
With the half-time whistle nearing, Newcastle were dealt a tough blow as Culbreath opened the scoring for Leverkusen, guiding a clinical header from the right flank into the bottom left-hand corner.
In the 52nd minute, Newcastle conceded a second goal as Pohl doubled the hosts' advantage. After the Magpies were unable to clear their lines from a corner, the ball fell to Pohl inside the box before driving a low effort beyond Dowell.
Newcastle made a triple substitution after the hour mark as Mason Miley, younger brother of Magpies midfielder Lewis, was introduced to the field along with Kacey Wooster and Kyle Fitzgerald, with the latter creating a key opening in front of goal as the Irish winger's cross from the right byline was turned towards goal but somehow kept out by the Leverkusen defence inside a crowded penalty area.
United's youngsters were handed a lifeline in the 72nd minute as Fitzgerald pulled a goal back in impressive fashion, collecting the ball in the final third before the Galway-born youngster, making his first appearance since September following a long-term injury, arrowed a ferocious effort from the edge of the box into the roof of the net.
The visitors, however, were unable to inspire a late fightback and, despite five minutes of stoppage-time, United's final league phase fixture in this season's competition ended in defeat.
Newcastle United Under-19s: Roman Dowell, Leo Shahar (c), Isaac Moran, Logan Watts, Thomas Bryant (Dylan Charlton 28), Rory Finneran, Sam Alabi (Mason Miley 64), Sean Neave, Matheos Ferreira (Kyle Fitzgerald 64), Seung-soo Park (Sammy Pinnington 80), Joe Brayson (Kacey Wooster 64).
Subs not used: Tyler Jones, Oliver Holland, Baran Yildiz, Henry Johnson, Thomas Old.
