The in-form Isak's early opener - his 13th goal in 20 games so far this term - was followed up by a similar effort from United's Brazilian enforcer before the break as Eddie Howe's side turned in a fluent, impressive first half showing to put the game beyond the hosts at Old Trafford.
The result keeps the Magpies in fifth place in the Premier League table heading into January - just three points shy of a top four spot with half the campaign still to play.
In a remarkably one-sided first half, the hosts would not have been able to feel hard done by had the Magpies got close to double figures. It took just over three minutes for the first goal to arrive, with Bruno Guimarães spraying a pass out to Lewis Hall on the left. His cross took a deflection but Isak met it in space in the middle, directing his header downwards and into the net to register United's 20th goal of what has been a stunning December.
It could have been more. Joelinton couldn't find the target after Anthony Gordon had turned Noussair Mazraoui, before the former Everton man volleyed over from a tight angle after meeting Jacob Murphy's deep cross. A rapid break, started by Guimarães' long, raking pass, gave Isak a golden opportunity, but he elected to try to chip André Onana and it didn't work, with the Red Devils' stopper standing up to it.
Just before the 20-minute mark, Howe's men had a second. Gordon turned provider from the left, with Joelinton attacking his inswinging cross under pressure from Lisandro Martinez. The ball may have gone it off his shoulder but it was no less than the visitors deserved for their total dominance, which had left Ruben Amorim's side looking very short of ideas.
The pressure continued, with Hall testing Onana from range, Tonali seeing his effort deflected wide and Isak thumping home what he thought was an emphatic third before being denied by a correct, and clear, offside call. Undeterred, they came again moments later, with a flowing move culminating in Tonali striking the base of the post from close range. It would have been a wonderful goal, coming as it did after some intricate work on the edge of the area.
Manchester United did have two opportunities before the end of the half, which were their only two efforts on goal in the opening 45 minutes. The first fell to Rasmus Højlund, who dinked just wide when one-on-one with Martin Dúbravka, and the second fell to Casemiro, who somehow skewed wide when substitute Kobbie Mainoo - introduced early in a bid to stem the flow of Newcastle's attacks - teed him up in stoppage time.
After the restart, there was a rally from the Red Devils. Højlund's attempts to get on the end of a cross into the box were foiled by Fabian Schär's timely intervention, and Amad Diallo saw a shot charged down from around 20 yards out. They began to enjoy more of the ball, and Mainoo saw one goalbound shot blocked before it could trouble Dúbravka. Those in red shirts were further encouraged by Harry Maguire's diving header, which struck the bottom of Dúbravka's right-hand post, with Hall producing a crucial block to deny Matthijs de Ligt on the rebound.
Another substitute, Leny Yoro, glanced a Christian Eriksen corner just wide inside the final 20 minutes, but while the Magpies didn't shift through the gears in quite the same way as they did in the first half, this was still about as comfortable a victory as Howe could have hoped for to round off the calendar year on a high.
