Marcus Rashford fired home United’s third after a swift counter-attack and with the Spaniards well beaten, Daniel James raced clear in the last minute to add a fourth goal for Ole Gunnar Solskjaer’s side.
Spurs also look to have wrapped up their round-of-32 tie after cruising to a 4-1 win against Austrian side Wolfsberger in Budapest.
Heung-Min Son, Gareth Bale and Lucas Moura were all on target as Tottenham took control before half-time at the Puskas Arena.
Pierre-Emerick Aubameyang was guilty of missing a number of chances as Arsenal had to settle for a draw in the first leg of their tie against Benfica.
With the game being played at Rome’s Stadio Olimpico due to travel restrictions, the Gunners were classed as the away side and should have left Italy with a win.
Instead, Bukayo Saka’s sixth goal of the season rescued a 1-1 draw after Pizzi had put Benfica ahead from the penalty spot.
Meanwhile, Borna Barisic’s spot-kick double ensured Steven Gerrard’s team survived a roller-coaster match to edge out Royal Antwerp 4-3 in Belgium.
In a clash that had everything, Scotland’s champions-elect held their nerve to salvage their unbeaten run in continental action this term and claim a vital first-leg lead.
Europa League 2020/21 round-of-32 results (first leg)
Dynamo Kiev 1-1 Club Brugge
Krasnodar 2-3 Dinamo Zagreb
Olympiakos 4-2 PSV Eindhoven
Red Star Belgrade 2-2 AC Milan
Slavia Prague 0-0 Leicester
Young Boys 4-3 Bayer Leverkusen
Maccabi Tel Aviv 0-2 Shakhtar Donetsk