These two giants of the game have met on 10 occasions in Europe, and rarely have they disappointed.
United were no match for the great Milan teams of the noughties, but got their own back on the last two times these sides met.
Their battle for supremacy over one another is finely poised with five victories apiece since that first meeting all the way back in 1958.
As they prepare to face off once again in tonight’s Europa League last-16 first leg, Sportsmail delves into the history books to pick out their classic encounters of yesteryear.
Ole Gunnar Solskjaer’s Manchester United face AC Milan in the Europa League tonight
The Hernan Crespo tie
Manchester United and AC Milan had two of the best squads in the world when they collided in the Champions League round of 16 in 2005.
United had a dream attack consisting of Cristiano Ronaldo, Wayne Rooney and Ruud Van Nistelrooy while Milan had a world star in every position. It truly was the Clash of the Titans.
For all of United’s great attacking qualities, Sir Alex Ferguson’s men were still unable to breach the Milan goal across two legs. They had Milan’s blasted centre-back pairing of Paolo Maldini and Alessandro Nesta to thank for that.
On the face of it, United’s exit seemed tame but in truth the two matches were close and decided by one man.
Hernan Crespo stole the tie in 2005, scoring in the first and second leg to put Milan through
Crespo netted the only goal at Old Trafford after a mistake from goalkeeper Roy Carroll
The first leg at Old Trafford was a night Roy Carroll would love to forget as it was his mistake that handed Milan victory on a plate.
When he failed to hold on to a speculative shot from Clarence Seedorf, Hernan Crespo arrived right on queue to gobble up the chance to tap in from close with just 12 minutes remaining on the clock.
United arrived at the San Siro two weeks later with a hill to climb rather than a mountain. It was backs against the walls but achievable.
That was until shortly after the hour mark, when Crespo headed in to consolidate their lead and send the Milan fans into raptures. There was to be no valiant comeback from United, this would be the end of the road for them while Milan would go on to march their way into the final.
Of course this brilliant side would meet their match on a famous night in Istanbul a few months later.
Despite having Ronaldo and Rooney in attack, United failed to score across the two legs
Milan’s brilliant 2005 team featured Dida, Kaka, Andrea Pirlo and Alessandro Nesta (pictured)
Kaka’s 2007 masterclass
Enter Kaka’s name alongside Old Trafford on YouTube and you are met with endless compilation videos.
That, as much as any, is a good indication of how special his performance was that night in Manchester, particularly when he ended up on the losing side!
Although Wayne Rooney scored a brace and a last-gasp winner in that first-leg game, it will always be remembered for Kaka – perhaps that is also because the outcome at Old Trafford would ultimately have no bearing on the end result.
The Brazilian was at the peak of his powers when these two met in Manchester in 2007 and was far too good for United’s defenders.
His first goal on 22 minutes to equalise, when he burst past Gabriel Heinze and slotted into the opposite corner with his weaker foot, was a sign of things to come.
Kaka put on a masterclass display at Old Trafford when the sides met again two years later
The Brazilian forward scored a memorable individual goal in the first leg at Old Trafford
It would get more embarrassing than that for Heinze and Co. 15 minutes later, Kaka latched on to a long ball forward.
Realising he had little support the Brazilian decided to go alone, nodding the ball past Darren Fletcher before clipping over Heinze’s head, drawing in Patrice Evra.
The United defenders tried to clear the ball, but Kaka was too quick, heading through the middle of them, causing Heinze and Evra to comically crash into each other as he ran around them and slotted into the corner past Edwin van der Sar.
It was vintage Kaka and pure individual brilliance. A second-half brace from Rooney would momentarily undo all of his good work until the return leg in Milan.
Kaka would score again that night, his opener opening the floodgates with Seedorf and Alberto Gilardino completing a comfortable 3-0 victory to put Milan through. Ferguson said ‘we cut our own throats with our defending’ afterwards, but the difference really was Kaka.
He toyed with United’s defenders all game and scored this equaliser before his solo effort
Kaka also netted in the return fixture as Milan overturned a one-goal deficit to progress
The night United put Beckham and Ronaldinho to the sword
It was not the Milan team of old that arrived at Old Trafford in 2010, but it featured stars like David Beckham, Ronaldinho, Andrea Pirlo, Klaas-Jan Huntelaar and Thiago Silva.
Dida, Gattuso, Seedorf and Filipo Inzaghi were in the squad, too.
So enough quality to give United a run for their money at the very least.
But Milan ended up leaving Manchester with their tails between the legs after being handed a real thumping.
The first leg had been competitive, United edging out Milan 3-2 at the San Siro, but this was a whitewash.
Ronaldinho (left) and David Beckham suffered a humiliating defeat at Old Trafford with Milan
Wayne Rooney headed in the opener before tapping in a delicious pass from Nani
United were pretty much dominant from start to finish. Rooney kicked off the proceedings, heading in the opener from Gary Neville’s whipped cross.
If Neville’s delivery was on the money, then Nani’s was even better when he got in down the left and put a delicious pass with the outside of his boot across the box for Rooney to tap in for his second.
Park Ji-sung scored the third, firing into the corner on the angle after Paul Scholes had feigned to shoot and slipped the ball into his path.
Beckham came off the bench in the second half and almost scored a screamer but his first-time volley from distance was well denied by van der Sar.
Darren Fletcher completed the rout, nodding in at the back post to inflict more misery on Milan.
Beckham and Ronaldinho cut despondent figures as the final whistle approached. Two greats of the game had been slain and put to the sword.
Park Ji-Sung scored United’s third goal on the night, squeezing his shot into the far corner
Darren Fletcher added insult to injury for Milan by heading in a late fourth for United
Busby’s United defy the odds
Three months and a day after the Munich air disaster had killed eight Manchester United players, Matt Busby’s men did the impossible by defeating AC Milan in the first leg of their European Cup semi-final.
Just months before, Busby was propped up in a Munich hospital bed being read his last rites. Now here was his side claiming a famous victory over the great AC Milan.
Harry Gregg, Bill Foulkes, Kenny Morgans and Dennis Viollet, all survivors from the crash, started that night and Viollet even scored.
Ernie Taylor got the other for United in a 2-1 win.
Manchester United keeper Harry Gregg, who was a survivor of the Munich air disaster, is pictured punching the ball clear during their 2-1 win over Milan months after the plane crash
United’s team line-up is pictured for the semi-final return leg in Milan, which they lost 4-0
Busby, who had summoned the strength to attend the FA Cup final defeat against Bolton a few weeks earlier, did not travel or the return leg, instead listening on the wireless as his side were well beaten 4-0.
A 5-2 loss on aggregate meant United would not progress but that first-leg victory will never be forgotten.
The 1958 semi-final also marked the beginning of United and Milan’s wonderful European rivalry.