They have met a couple of times in cup competitions over the last 16 years but nothing quite compares to a top flight clash.
Leeds were relegated from the Premier League in 2004 and dropped to the depths of League One before clawing their way back up.
The two clubs had a feisty and often bitter rivalry over the years going back to the days when Matt Busby and Don Revie were in opposite dugouts.
It intensified in the Premier League era when Eric Cantona swapped Elland Road for Old Trafford while Roy Keane's personal vendetta against Alf-Inge Haaland started when the father of Erling Haaland played for Leeds.
Whites fans will also remember the day Alan Smith controversially signed for Manchester United following Leeds' relegation from the Premier League.
Smith was a local lad who vowed to stay at Elland Road despite the relegation but just a matter of weeks later he was being unveiled at their bitter rivals.
There will be plenty of Leeds fans out there who are still to forgive Smith for crossing the divide and joining United, particularly after previous comments and actions made.
He was even seen crying and kissing the Leeds badge on the day they were sent down from the Premier League in 2004 when they drew 3-3 with Charlton.
When asked by Soccer AM in 2002 if there was a team he'd never player for, he said: "Yeah, Man United."
Yet despite the controversy, his move contributed to his boyhood club avoiding liquidation.
The Yorkshire club were in dire financial trouble and desperately needed the money. The best offer for Smith was from Man United and so he went there.
"Leeds fans didn't want him to go there but as far as the club is concerned, Alan Smith going there probably saved us from going into administration or liquidation a lot earlier than we did," Peter Lorimer said.
Sir Alex Ferguson and co. were the only club willing to pay the £7m transfer fee in full rather than spread out payments.
"I've always said I wanted to stay here until it was no longer possible and I think that's the situation we're approaching now," said Smith at the time.
"Everyone appreciates that from the financial side, the club's side and from my point of view it's time to move on."
If if he'd refused a move then it could have had dire consequences. The fact of the matter was that Leeds could not afford the wages of star players like Smith, James Milner and Mark Viduka.
All were sold to keep the club from going out of business.
In the years following, he told the Official Utd podcast : "For me, it wasn't even a rivalry anymore.
"If you aren't in the same league, I don't see how it can be.
"I would have been doing myself a disservice if I took the easy option and didn't sign for — arguably at that time — the biggest club in the world."
Not all Leeds fans would see it that way, though, after being such a fan favourite over the years playing 228 times following a debut in 1998.
Dominic Matteo also left the club that summer and joined Blackburn and the pair ended up living close to each other.
When speaking about Smith's transfer, Matteo told The Athletic : "It was funny, though, because when it came to the Man United move, we didn't broach the subject much. I tried not to get into it with him because I could tell how difficult it was going to be.
"Looking from the outside, it seemed like a seriously tough call. He's a Leeds fan who's just seen his club go down being offered the chance to go to one of the biggest clubs in Europe but a club who people in Leeds have no time for. It was obvious what the reaction would be.
"Smithy was always a bit of a loner and always a bit different to your average footballer. He liked what he liked, he kept himself to himself quite a lot and he seemed pretty happy in his own world.
"That Leeds squad loved a drink but he wasn't into alcohol at all. He never touched it, which is just how he was. I knew the transfer was a personal thing so I didn't want to make it any more difficult by trying to chat it over. It was best to leave it. Not my business."
Smith was primarily used as a striker at Leeds but found himself with a slightly different role at United.
He was seen as a possible successor to Roy Keane at Old Trafford and was being groomed to take over from the Republic of Ireland international.
In 2005, Sir Alex Ferguson said: "Roy sees characteristics in Alan that he saw in himself as a young player, which could help Alan develop into a very good player in that position."
Things didn't quite work out the way at Old Trafford for Smith, though, with a horror injury that kept him out injured for a significant amount of time.
He broke his leg and dislocated his ankle while blocking a John Arne Riise free-kick in February 2006.
"When I looked, the leg was lying one way and my ankle was pointing towards Hong Kong so I knew I was in serious trouble," Smith told The Sun.
United boss Ferguson said of the injury: "It's one of the worst I've seen. It's a very long-term injury."
His time at Manchester United would not last much longer and joined Newcastle in 2007 before working his way down the leagues with MK Dons and finally Notts County.
Manchester United and Leeds re-ignite their rivalry on Sunday when the two clubs meet for the first in the Premier League since 2004.