Ole Gunnar Solskjaer's Reds will face the current leaders of La Liga, who include former Red Adnan Januzaj and ex-Manchester City star David Silva in their ranks.
The two clubs have only met twice before - in the 2013/14 Champions League group stage. Both fixtures were low-scoring affairs, with United winning 1-0 at home before a goalless draw in Spain. Inigo Martinez's early own-goal at Old Trafford proved to be the decider, handing David Moyes's men three points.
The first leg is away from home on Thursday 18 February 2021, before the return takes place a week later at Old Trafford.