During the 1990s and early 2000s, the Magpies were regular competitors at the top of the league, and these two served up some classic clashes.
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But under Mike Ashley's ownership, there was a rapid decline as the Toon went from being a club wanting to compete to one happy to survive.
That attitude led to two relegations and one top-five finish in Ashley's 14-year ownership of the club.
But now, the club has been transformed in just over a year after a takeover by a Saudi-backed consortium, and the Toon could leapfrog their opponents with a win at Old Trafford on Sunday.
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This is a far cry from the last time the Magpies visited the red side of Manchester.
In September 2021, Manchester United welcomed Newcastle as Cristiano Ronaldo returned to the club after 12 years away.
The Portuguese superstar scored twice in a 4-1 thrashing for Steve Bruce's side.
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At that point, it looked like it was going to be a long season for the Toon and a relegation battle seemed almost certain.
In the end, everything changed, and Newcastle stayed up comfortably, but in just over a year, it is crazy to see how much the team has changed, not just in personnel but in performances.
For a start, manager Eddie Howe has abandoned the back five, while the whole defence has changed.
Freddie Woodman, Ciaran Clark and Issac Hayden are no longer with the Magpies. Woodman has joined Preston North End permanently, while Hayden and Clark are on loan with Norwich City and Sheffield United, respectively.
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Javier Manquillo actually scored in this game for Newcastle but hasn't played for the Magpies since he started the 5-1 loss to Tottenham in April.
Jamaal Lascelles is still club captain but now finds himself the fourth-choice centre-back, yet he still plays a massive role in the dressing room.
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And Matt Ritchie hasn't started for the Magpies since he played 90 minutes against Manchester City in a 4-0 defeat in December.
Fabian Schar was actually on the bench that day against the Red Devils but has played in 30 of Howe's 35 Premier League games as Newcastle boss.
The Swiss international is now a key player in the new system.
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Kieran Trippier will almost certainly start at right-back and the England international is a class act.
The former Tottenham man is one of Newcastle's best players and is a constant threat from set-pieces and crosses.
No player in the league has created more chances from set plays (11) or played more passes into the opposition box (124).
Sven Botman and Dan Burn are likely to partner Schar at the back with Nick Pope in goal.
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Pope has been one of the signings of the summer and has already made a succession of top saves, while Botman has looked at ease in the top-flight, dominating against Aleksandar Mitrovic and Ivan Toney, among others.
Burn has also proved to be a shrewd signing, and as a boyhood Toon fan, he must be living the dream.
In midfield and on the wings, not many of the players have changed, but their performances certainly have.
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Joelinton, signed as a striker, was a flop under Bruce; he scored six Premier League goals and looked lost.
But Howe has turned the Brazilian into a box-to-box midfielder who loves his new role.
Joelinton averages 2.3 tackles and 1.3 interceptions per game this year but also records 1.4 key passes and completes 2.1 dribbles per match.
He has become a new player.
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The same can be said of Miguel Almiron, who has already matched his best Premier League goal tally this season with four in his first nine league games.
Again, the Paraguayan struggled to deliver any end product for a long time, but after Jack Grealish's comments about him this year, he has stepped up.
Almiron's pace and work rate are perfect for Newcastle's new approach, and he is the Toon's top scorer this season, and that's something no one on Tyneside was expecting to see at any point.
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Joe Willock and Jacob Murphy are players who have had ups and downs in their time on Tyneside.
However, they are now turning in consistent performances.
Willock hasn't scored for the Magpies since February, but his all-round displays have steadily improved.
He has completed 84 per cent of his passes under pressure this season and is averaging 1.3 key passes per game.
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If he keeps playing like this, the goals will surely follow.
And Murphy has stepped in for Allan Saint-Maximin and has provided a constant threat down the left.
Of course, the Frenchman is a born match-winner, but he has suffered a setback and looks likely to miss the trip to Old Trafford.
Therefore, the former Norwich City man will get the chance to impress once again.
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Then we have Bruno Guimaraes. The Brazilian international has made the Premier League look easy since he joined from Lyon.
No Newcastle player has scored more league goals (7) since his arrival, while he has embraced life on Tyneside and is a definite fan-favourite.
Many would argue he has been the most transformative signing, and he will play a key role if the Toon are to win on Sunday.
Another major difference is in the striking department.
Last year, Saint-Maximin started as the lone striker, but Callum Wilson will get the nod this time.
The England international has had his problems with injuries, but he has bagged 23 goals in 49 Premier League appearances for the Toon, including five in his last eight.
Record signing Alexander Isak won't make this one, but once fit, Newcastle possess some serious firepower.
But despite all this, the Toon have only beaten Man United at Old Trafford once in their last 37 visits.
However, you would have to say this is the best chance Newcastle have had in a long time to take three points and continue their great resurgence under Howe.