It will be their first meeting with the nine-times winners since Brazil striker Ronaldo scored a hat-trick at Old Trafford in 2003.
In addition, it confirms the return of Cristiano Ronaldo to the club where he spent six successful seasons and became the best player on the planet, not to mention Jose Mourinho's presence on the where ground he famously announced himself to British audiences whilst at Porto.
Here, we look at the great United meetings with Real from the past.
11 April 1957 - Real Madrid 3 Manchester United 1
The Busby Babes' European baptism in front of 135,000 at the Bernabeu. Alfredo di Stefano was at his majestic best, scoring the second goal as Real cruised into a semi-final lead. A late Tommy Taylor header appeared to give United hope but Enrique Mateos scored again for the Spanish giants.
25 April 1957 - Manchester United 2 Real Madrid 2
Any hope United had of getting through was extinguished when Di Stefano opened the scoring at Old Trafford. The Red Devils were two down before Tommy Taylor and Bobby Charlton struck back. United went out but a European odyssey was born.
24 April 1968 - Manchester United 1 Real Madrid 0
Eleven years after their first semi-final meeting, the two sides met again. Matt Busby's side were at home first and grabbed a crucial first-leg lead when George Best turned home John Aston's first-half cross.
15 May 1968 - Real Madrid 3 Manchester United 3
United seemed to be on their way out as the contest entered its final 20 minutes, with Real ahead on the night and in the tie. But David Sadler stunned Real when he pounced on George Best's free-kick before Munich survivor Bill Foulkes scored the most important goal of his United career to send Matt Busby's men through.
19 April 2000 - Manchester United 2 Real Madrid 3
After a goalless first leg, United were in confident mood ahead of their quarter-final decider. But those hopes were soon dashed as the visitors raced into a three-goal lead, rendering late efforts from David Beckham and Paul Scholes meaningless.
23 April 2003 - Manchester United 4 Real Madrid 3
After losing the first-leg 3-1, Sir Alex Ferguson dropped a bombshell by leaving out Beckham. It did not work on any level for the United boss. Three times Real led, with Ronaldo scoring a hat-trick before leaving to a standing ovation. Beckham's introduction triggered a comeback of sorts but the England man's brace just left his manager even more red-faced.