Harvey Barnes' half-volley had given Eddie Howe's side a half time lead at St. James' Park, but by the time Dan Burn turned Brennan Johnson's effort into his own goal on 56 minutes the visitors looked the likelier side to snatch a winner.
But instead it was the Magpies who prevailed, as Jacob Murphy teed up Isak to roll home a winner with 12 minutes left and maintain United's 100 per cent win record at home this term.
A relatively cagey first half began with the hosts in the ascendency. Isak robbed Son Heung-min on the right and looked to loft one into the box, but his cross-shot ended up clipping the crossbar. Another swift break led to Barnes cutting in from the left and whipping a shot just beyond the post, with goalkeeper Guglielmo Vicario beaten.
Spurs had the ball in the net soon after, with Cristian Romero nodding in a James Maddison cross from the right, but it was ruled out; the centre back was well offside. It preceded a spell of pressure from the visitors, though - Nick Pope was twice called into action to deny Pape Matar Sarr, who thumped two goalbound efforts his way from 25 yards. Both were well kept out by the England stopper, who was recalled to the Three Lions' squad earlier this week.
Eight minutes before the break, Howe's men made the breakthrough. It was a brilliantly-taken goal from Barnes, who met Kelly's tempting cross from the left, guiding a first-time finish into the far corner to give United a lead they held until the break.
A timely Radu Dragusin challenge prevented Isak from shooting after the restart, with the Swedish forward's appeals for a penalty waved away. At the other end, Spurs - who had threatened only sporadically up to that point - wasted a golden opportunity when substitute Johnson's deflected cross found Wilson Odobert at the far post, but he somehow missed the target from close range.
Ange Postecoglou's side were firmly on top in the second half's opening exchanges. They could have levelled before they did, when Pedro Porro's delivery almost caught the Magpies out as it crashed off the woodwork. But it felt as though a Spurs response was coming, and in the end it came in disappointing fashion for Newcastle. Maddison's shot was pushed away by Pope, but only as far as Johnson, whose attempt at full stretch was inadvertently turned in by Burn in a last-ditch attempt to clear it off the goalline.
Howe sent on Murphy for Barnes and after some neat work from Isak and Anthony Gordon, the winger tested Vicario, forcing him to save smartly at his near post. The introduction of Sandro Tonali brought a terrific reception from United fans, but Spurs continued to dominate. Only the backtracking Bruno Guimarães prevented Son from tapping in after Johnson's breakaway, while Pope again made two crucial saves - first from Maddison's 20-yarder that was heading for the top corner, and then from Porro's dipping drive from similar range.
But against the run of play, Newcastle mustered a winner with a fine move, which started with Joelinton in his own half. His sharp turn and through ball released Murphy, who unselfishly squared the ball for Isak to tap into an empty net and make it two home Premier League wins in as many games for Howe's unbeaten side.
