The substitute's strike came in the eighth minute of added time - a minimum of five had been signalled by fourth official David Coote - and was a disappointing finish to a night which at one stage looked set to be all about Isak.
He had only been cleared to play hours earlier, when his international clearance was finally received on the afternoon of the game, but - with Allan Saint-Maximin, Bruno Guimarães, Callum Wilson and Jonjo Shelvey all missing due to injury - the Swedish star went straight into Eddie Howe's starting line-up.
And he wasted little time in giving the sold-out away end a glimpse of his qualities as, in the 11th minute, he jinked inside and unleashed a strike from the edge of the penalty area, but it flew over the bar.
Seven minutes later, with United looking compact and slick on the counter, Matt Targett rolled the ball into Ryan Fraser, whose wonderful first touch on the spin teed him up for a blistering shot which went narrowly off target.
Dan Burn made a vital interception to take the ball off the toe of Mohamed Salah after Luis Díaz had twisted and turned and cut the ball back from the byline, but Newcastle remained the more dangerous side and when Joe Willock was fouled on the edge of the box, Kieran Trippier was presented with a free kick from an almost ideal position for the England man - but sent his effort too close to Alisson.
In the 34th minute, a good Liverpool move culminated in Roberto Firmino finding Díaz, who rounded Nick Pope but, with two United defenders on the line, blazed wide.
There was no such prolificacy from Isak four minutes later. Trent Alexander-Arnold conceded possession and Willock spread play to Miguel Almirón, who in turn passed to Trippier. His ball found Sean Longstaff in a central area and the midfielder played a perfectly-weighted pass into the path of Isak, whose finish was superb, allowing him to race to celebrate with the travelling fans behind the net.
At the beginning of the second half, Willock bravely threw himself into the path of an Andrew Robertson shot before, moments later, Isak thought he had doubled United's lead and his own goal tally in black and white. He had shown great composure to finish after leaving two defenders on their backsides, but was offside by the narrowest of margins as he sprinted onto Fraser's ball.
Liverpool's first shot on target - a low Harvey Elliott effort which was held by Pope - arrived on the hour mark but their second, a minute later, resulted in the equaliser as the home side went from back to front in seconds, with Firmino sweeping home from Salah's cutback from the right.
In the 79th minute, Pope pushed an effort from the dangerous Díaz over the bar then two minutes later, held a deflected effort from the same player as the Reds went in search of a winner.
But two strikes from Fabinho - both off target - and a scuffed shot from substitute Fábio Carvalho were the closest they came until deep, deep into stoppage time.
United failed to clear their lines from a corner and Carvalho forced the ball home as the Magpies were beaten for the first time in 2022/23.
