Ronaldo broke the record for the longest gap between Premier League appearances (12 years and 118 days) and struck either half for United, cancelling out Javier Manquillo's initial equaliser, as countryman Bruno Fernandes and Jesse Lingard also got on the scoresheet in a 4-1 win.
The result sees United climb to the top of the Premier League table, still unbeaten after four matches played, while Newcastle, in their 1,000th top-flight match, drop to 19th with just one point.
Story of the game
Ole Gunnar Solksjaer made two changes from the 1-0 win at Wolves, as Nemanja Matic replaced Fred in midfield and the other big news which everyone at the Theatre of Dreams eagerly anticipated was seeing Ronaldo lead the line in place of the recently departed Dan James and make his first appearance for the club for 12 years, since re-joining from Juventus.
Meanwhile, Steve Bruce made four changes to his Newcastle side that drew 2-2 against Southampton. Manquillo, Isaac Hayden and Ciaran Clark replaced Jacob Murphy, Federico Fernandez, and Fabian Schar in defence and Joelinton was handed a start in place of the injured Callum Wilson. Noticeably, goalkeeper Karl Darlow returned to the bench with Freddie Woodman keeping his place in between the sticks.
Unsurprisingly, ahead of kick-off, all eyes were on one of the world's greatest ever players of all time, and once Ronaldo's name was read out in the starting line-ups, the Portuguese phenomenon was greeted with a rapturous reception from the supporters inside Old Trafford.
There was a minute's applause prior to kick-off to mark the 20th anniversary of the 9/11 terror attacks.
The Red Devils made a bright start and within four minutes, Ronaldo was almost put through on goal by countryman Bruno Fernandes, but his touch let him down and the ball got away from him.
At the other end, just a minute later, Joelinton was picked out by Allan Saint-Maximin and the Brazilian got the better of Harry Maguire and Raphael Varane but fired his shot from the edge of the area well wide in front of the Stretford End.
Ronaldo's movement was causing Newcastle all sorts of problems and his trickery with his feet helped him buy a yard of space in the penalty area though he crashed his effort into the side-netting.
On 19 minutes, United came close to a breakthrough when Varane met Luke Shaw's corner with a towering header but the ball whistled just past the far post.
Newcastle showed they can also be a threat as David de Gea was forced into his first save when Matt Ritchie's deflected shot from the edge of the box was gathered with ease by the Spaniard. A few moments later a sloppy mistake at the back from Fernandes gifted Joe Willock the ball but the midfielder failed to capitalise and fired over the bar.
The hosts, as you would expect, controlled the possession and carved out another big chance midway through the first half when Fernandes took aim from 25 yards and his mis-hit strike fell to Jadon Sancho, who got a touch on the ball but diverted his shot wide of the post.
In a wide open game, United's first shot on target came from Maguire as the England defender got on the end of Shaw's delivery and headed straight into the gloves of Woodman.
It looked like Newcastle were set to go in at the interval goalless at Old Trafford but in the blink of an eye, with the last kick of the half, United broke the deadlock as Mason Greenwood's shot took a slight deflection, and Woodman spilled the ball in the six yard box and Ronaldo reacted quickest to bundle home and get his second debut off to the perfect start.
United began the second half dictating the flow of the game and Aaron Wan-Bissaka's dangerous cross into the six-yard box was unable to be turned home by Ronaldo or Sancho.
Despite trailing, Bruce's side showed no fear and were looking to catch the hosts out on the counter-attack. Incredibly, on 56 minutes, they did just that as Miguel Almiron won the ball inside his own half, drove forward, before laying it off to Saint-Maximin, who slid in Manquillo on the right and the right-back finished confidently into the far corner.
But the lead lasted just six minutes, as once again Ronaldo proved to be a thorn among the Newcastle defence as Shaw cleverly slotted the ball into his path, and after holding off Hayden, the forward drilled a low shot in between the legs of Woodman before wheeling away in celebration as Old Trafford erupted.
To Newcastle's credit, they were not letting United stroll to victory, and instead were searching for another equaliser as Joelinton held off challenges of Wan-Bissaka and Varane before stinging the palms of De Gea.
Though, Solksjaer's side added a decisive third with 10 minutes remaining and it arrived in some style from another Portuguese playmaker. Fernandes received the ball from Paul Pogba and curled a sensational 30-yard effort past Woodman.
And United were not finished there as in stoppage-time, substitute Lingard, who replaced Sancho, finished off a well worked move to send his side top of the table.
The Portuguese stars steal the spotlight
In similar fashion to his hat-trick against The Magpies 13 years ago, Ronaldo, now at 36-years-old proved he's not lost his magical touch and can still play at the highest level. He was a constant menace with his fancy footwork and his international team-mate Fernandes also deserves some high recognition, as he produced the goal of the game. After climbing to the top of the table, albeit after four games, Solksjaer's side look capable in mounting a genuine title fight this season.
Newcastle battled bravely but lack of transfer activity a cause for concern
It was always going to be a tough ask for Newcastle this afternoon and it was a valiant effort from Bruce's side. They never gave in. The scoreline was perhaps harsh on the visitors as they had chances to score but ultimately, the quality and clinical edge between the two sides played a significant role in the margin of victory.
With what appeared to be worrying signs for Newcastle fans when Willock limped off injured late on, The Magpies will be hoping it's nothing serious. The failure to not bring in one or two loan additions in the summer could certainly come back to bite them, in what's already a very light squad.
Manchester United: De Gea; Wan-Bissaka, Varane, Maguire, Shaw; Pogba, Matic; Greenwood, Fernandes, Sancho; Ronaldo. (4-2-3-1)
Newcastle United: Woodman; Manquillo, Hayden, Lascelles, Clark, Ritchie; Willock, Longstaff, Almiron; Joelinton, Saint-Maximin. (5-3-2)