The Magpies conceded twice within the space of six first-half minutes, with Sven Botman's unfortunate own goal sending Newcastle behind in the capital before Arsenal swiftly doubled their advantage following Kai Havertz's close-range finish.
Newcastle, who had won once in their previous 12 Premier League trips to the Emirates Stadium ahead of this evening's encounter, fell further behind in the second half following quick-fire goals from Bukayo Saka and Jakub Kiwior before Joe Willock's late header proved a mere consolation on an otherwise difficult evening for Eddie Howe's side.
The Newcastle boss made three changes to the starting XI which claimed a 2-2 draw against AFC Bournemouth last weekend as Loris Karius was handed his first competitive start for the Magpies since last year's Carabao Cup final against Manchester United, replacing the ill Martin Dúbravka, while Alexander Isak and Tino Livramento were also handed starts in place of Harvey Barnes and Dan Burn respectively.
Karius, making his first Premier League outing since May 2018, produced a key save to prevent Declan Rice sending the Gunners ahead in the opening exchanges, with the central midfielder's fierce drive at goal beaten away by the German goalkeeper.
In the 18th minute, Arsenal took the lead through Botman's own goal. After Gabriel's towering header from Saka's in-swinging corner was initially saved by Karius, Livramento's attempted clearance from the goal line struck Botman's knee before narrowly crossing the line.
Newcastle were delivered a further blow six minutes later as Havertz extended the hosts' lead. After Martinelli latched onto Jorginho's lofted pass inside the box, the Brazilian's cutback from the byline found its way to the Germany international, who tucked a low first-time effort into the net from close-range.
Martinelli almost turned from provider to goalscorer as the South American forward connected with Saka's cross after dangerous build-up play with the latter and Arsenal captain Martin Ødegaard but directed his header over the crossbar.
Karius produced a strong stop to deny Saka from adding a third goal for the Gunners, reacting quickly to push away the England international's stinging goal bound drive.
Anthony Gordon, celebrating his 23rd birthday today, produced United's first shot on target shortly after the restart, cutting inside from the left flank before his low drive at goal was held by Arsenal goalkeeper David Raya.
Isak was unable to halve the deficit shortly after the hour mark as the Swedish frontman collected Bruno Guimarães' diagonal pass before his powerful attempt at goal flashed wide of the target.
In the 65th minute, Saka netted the hosts' third of the evening after cutting back inside the penalty area before curling a low effort into the bottom left-hand corner.
Arsenal grabbed a fourth four minutes later through Kiwior as the Polish full-back got onto the end of Rice's inviting corner before directing a deft header into the net.
In the 84th minute, Newcastle netted their first goal at the Emirates Stadium since December 2014 as Willock, introduced from the substitutes' bench, pulled a goal back against his former club.
After fellow substitute Dan Burn raced onto Gordon's pass, the left-back's cross was directed into the central midfielder's path, who looped the ball over Raya via the right-hand post on his first United appearance since November following a long-term injury.
