Anel Ahmedhodzic's header gave the struggling Blades the lead early on at St. James' Park, but Isak's typically cool finish levelled matters in a nervy first half.
And after the restart, a diving header from Bruno Guimarães, a penalty from Isak, a Ben Osborn own goal and an emphatic Callum Wilson finish eased the Magpies past the visitors, confirming their relegation from the Premier League - but, crucially, boosting Eddie Howe's side's hopes of securing qualification for Europe in the process.
The hosts fell behind to Ahmedhodzic's header in the Blades' first attack of the afternoon. It came following a pinpoint, inswinging cross from Gustavo Hamer, who picked out the centre half in the box and his header was firm and low, beating Martin Dúbravka.
Newcastle looked to respond swiftly, with Sean Longstaff seeing a shot blocked and Jacob Murphy curling wide, but the next best opening fell the way of the visitors. Cameron Archer could have made it two after cutting in from the left and shooting, but Dan Burn got across just in time, throwing himself in the way of the shot.
Longstaff saw another effort charged down and at the other end, Ben Brereton Diaz stung Dúbravka's palms with an angled drive, but one moment of quality was all it took for the Magpies to draw level. Murphy's neat through ball down the right channel was perfect for Isak, whose low, first-time finish was unerring.
The Swedish forward fired wide again but Chris Wilder's side rallied. Ahmedhodzic threaded a pass through for Brereton Diaz, who rounded Dúbravka but found Burn sliding in, once again, at the critical moment to block his goalbound shot. From the resulting corner, only Hamer and Andre Brooks will know how they didn't retake the lead; the former's close range header came back off the crossbar, and in the moments that followed, Brooks somehow slashed wide of the target from a similarly good position.
Lewis Hall tested Wes Foderingham in the final seconds of a difficult half for Howe's men, who struggled to build any real momentum before the break. The Blades, meanwhile, continued to push on the counter after the restart, with a Brooks run and shot in the second period's early exchanges a warning of their threat.
But with 53 minutes gone, a set piece prised Sheffield United open, and Guimarães was the beneficiary. Brereton Diaz's foul on Tino Livramento gave Anthony Gordon the chance to whip a free kick to the far post, where the Brazilian was waiting to dispatch it with a diving header in front of the Gallowgate End.
A breakaway led by Hamer resulted in Dúbravka parrying Brereton Diaz's shot but hopes of a Blades comeback were dashed when Mason Holgate bundled into Gordon in the box shortly before the hour. It was a clumsy challenge and it was punished in clinical fashion by Isak, who rolled home from the spot, extinguishing any fears of an unlikely comeback and reasserting Newcastle's dominance as the contest opened up.
Things got worse for Wilder's side when Osborn inadvertently backheeled into his own goal in the midst of a goalmouth scramble and by the time substitute Wilson rattled home a fifth with just under 20 minutes remaining, the writing was on the wall for the Blades, whose relegation was confirmed - shortly after they were denied a penalty late on, when young defender Alex Murphy's challenge on Jaden Bogle was deemed fair after a VAR check.
The win leaves Howe's men in seventh place in the Premier League table as of Saturday evening, with four games left to play and plenty still up for grabs for those in black and white.
