Anthony Gordon's second-half strike was the only goal of the night, but in truth the margin could have been far more emphatic as the Magpies continue to find ways to win despite their lengthy injury list - which grew further when Nick Pope was forced off late on with a shoulder problem.
Newcastle, unchanged for a third game in a row, dominated from the first whistle, with Diogo Dalot almost turning a deflected pass from Gordon into his own net in the opening minutes.
The ball appeared to strike the Portuguese defender's arm, albeit unintentionally, but unlike the decision which went against Eddie Howe's men in Paris in midweek, there was no intervention from VAR.
In the 11th minute, in a rare forward foray from the visitors, Alejandro Garnacho saw a low shot blocked by the legs of Pope, but Newcastle were soon back on the front foot.
In the 17th minute, a fine move resulted in Miguel Almirón getting a shot away but André Onana pushed it out, then Gordon teed up Bruno Guimarães, whose effort from the edge of the box flew narrowly off target.
Isak was denied his tenth goal of the campaign in the 20th minute as Guimarães and Almirón combined only for the Swedish striker to see his close-range strike deflected behind by Harry Maguire, then Jamaal Lascelles headed over after the resulting corner was patiently worked towards the Magpies skipper via Fabian Schär and Isak.
Shortly after the half-hour mark Isak sent an effort wide, before, in the 35th minute, Kieran Trippier invited Almirón to gallop into the box but the Paraguayan's left-footed shot whistled just past the angle of post and bar at the Gallowgate End.
In the 39th minute, after Schär was fouled just outside the area, Trippier stepped up to cannon an almost-perfect free kick off the underside of the crossbar, then as half-time approached the excellent Tino Livramento saw a dangerous cross deflect into the side-netting and Schär had a shot blocked by Maguire.
The same player then curled wide just before the interval, with the Magpies extremely unfortunate not to go into the break in front.
And the game continued in the same vein in the second half, with a low cross from Guimarães taken off the toe of Isak by Maguire before Joelinton made space for a shot soon afterwards but sent it too close to Onana.
But the Manchester United goalkeeper was beaten seconds later, when Guimarães played the ball out to Trippier, whose low cross from the right was converted by Gordon; his sixth goal of the season was also his third in his last four league outings.
Schär sent a piledriver over the bar as Newcastle looked to double their advantage, then in the 79th minute, Lewis Miley looked set to score his first goal for his boyhood club after Joelinton's cut-back, only for Aaron Wan-Bissaka to make a superb block from the teenager.
At the other end, Schär made an equally impressive interception to keep out a Sergio Reguilon strike, but Pope was hurt as he dived and had to be helped from the field by club doctor Paul Catterson and physio Sean Beech.
Pope was replaced for the final stages by Martin Dúbravka, who spent part of last season on loan with Manchester United, and - after Maguire had an 89th-minute goal ruled off for offside and despite nine minutes of added time - he was able to help the Magpies to maintain their clean sheet and claim three points to move up to fifth.
