Despite four goals being scored in the previous 540 minutes of Premier League action between the two sides, Neal Maupay's brace in the opening seven minutes left Steve Bruce's side stunned at St. James' Park.
After the Frenchman broke the deadlock from the penalty spot shortly followed by a close-range finish, Aaron Connolly sealed the win for Brighton in the closing stages before the Seagulls were reduced to ten men following Yves Bissouma's straight red card.
The Magpies headed into the top-flight clash in the search of three successive wins in all competitions following last week's opening day win at West Ham United as well as booking their place in the Carabao Cup third round with a 1-0 victory against Blackburn Rovers.
However, the hosts got off to a disappointing start as Brighton were awarded a penalty in the 4th minute. After Tariq Lamptey advanced dangerously into the box, the teenage full-back was brought down by Allan Saint-Maximin, allowing Maupay to convert from 12 yards, firing his spot-kick down the middle of Karl Darlow's goal.
Only a few minutes had passed before United were left shocked again as, in the seventh minute, the Seagulls doubled their advantage.
The goal, originally ruled out as Leandro Trossard was adjudged to be slightly offside in the build-up, eventually stood after a lengthy VAR review, with the Belgian correctly judging his run before delivering a low cross into the path of Maupay, who steered the ball into the far corner.
It could have got worse for United after a swift counter-attack, orchestrated by the lively Lamptey, was vitally cut out by an important intervention from right-back Javier Manquillo.
Newcastle were restricted to clear-cut chances in front of goal as Callum Wilson, who netted on his United debut at West Ham United, was prevented from a goalscoring opportunity on his home bow at St. James' Park as Lamptey produced a crucial recovering challenge to halt the striker from firing a shot towards goal.
Newcastle were fortunate not to concede a third on the stroke of half-time as Lamptey, a constant threat in the first half, drilled a low strike towards Darlow, who managed to keep the ball out with his feet.
Shortly after the hour mark, United missed a golden chance to halve the deficit through Wilson. Miguel Almirón, introduced from the bench at the restart, sent an inviting ball from the left wing into the penalty area but the forward's free header was directed over the crossbar.
Newcastle almost conceded a third as Trossard drove towards the United defence before his low effort clipped the outside of Darlow's post.
However, Albion did extend their lead in the 83rd minute through Connolly. After picking up the ball on the edge of the penalty area, the Irishman opened his body up before tucking the ball into the far corner.
Graham Potter's side were reduced to ten men in the 89th minute as Bissouma's high foot caught Lewis directly in the face, leaving referee Kevin Friend no choice but to send off the Malian midfielder after another VAR check.
Newcastle United: Karl Darlow; Javier Manquillo, Jamaal Lascelles (c), Federico Fernández, Jamal Lewis; Jeff Hendrick, Jonjo Shelvey (Joelinton 72), Isaac Hayden, Allan Saint-Maximin (Ryan Fraser 33); Andy Carroll (Miguel Almirón 46), Callum Wilson.
Substitutes: Mark Gillespie, Ciaran Clark, Emil Krafth, Matt Ritchie.
