One person that has previous experience of that particular fixture is former Liverpool winger Steve McManaman, who came up against United on four occasions during his four-year stint at the Bernabeu.
Ahead of the first leg on Wednesday night, we caught up with ESPN analyst McManaman to preview the eagerly-anticipated match.
How do you see this match going. Is it too close to call?
"Hopefully it will be a high-scoring and exciting game. It's been well-documented that Madrid have got their own problems at the moment and United have been pretty impressive but it should be close.
"There are lots of different storylines that we can talk about. Cristiano Ronaldo going back and Jose Mourinho going back to England. They will probably dominate most of the headlines. I just hope that it will be two great encounters and I think they will be because it always is between those two."
You've played in this encounter four times. What are your memories from them? The Brazilian Ronaldo scored a hat-trick in one of those, so surely that is right up there?
"Great games and great atmospheres. It was different for me because I was a Scouser playing there. It was a different feeling for me because I had played against them many times before but I remember the Spanish players walking off the field and even though we had twice been successful in getting through, they adored Old Trafford.
"That was because of the noise of the place and the reception that they got. Even Ronaldo got applauded off the pitch when he was substituted. He couldn't believe it. They loved the atmosphere that the English supporters produce."
How are Man United viewed by Madrid? Are they seen as big rivals?
"Internationally, of course. Any club who want to dominate the world like Real Madrid or Manchester United and break into the Far East and Africa - they are always going to be compared. Who has got the most supporters, who made the most money last year - that sort of thing. There are a handful of teams that are now classed as the super teams and these two are up there."
Madrid have not won the Champions League since you were playing for them back in 2002. How do you rate their chances of ending that wait this year?
"They want to get to 10 European titles even though they are the most successful side in the competition. They need to win it again. However, it will be very hard for them to win it this year on current form. I think the outstanding teams in the Champions League are Barcelona and the German sides. They have been the most impressive out of what I have seen so far.
"Manchester United progressed from a relatively comfortable group, but the best football is being played by the likes of Bayern, who have gone slightly unnoticed because they haven't played any English teams. Dortmund were very impressive and of course Barcelona are always impressive, aren't they? Madrid will find it difficult, but they always save their best football for knockout competitions and that is what the Champions League is now."
ESPN continues its live Europa League coverage as Chelsea take on Sparta Prague on Thursday, February 14 at 5.30pm, followed by Newcastle United vs. Met'st Kharkiv at 8pm. For details please visit espn.co.uk/tv. To find out all the latest news and reaction on this season's Europa League competition visit espnfc.com.