Valencia matched the competition's record win, while Danish minnows Midtjylland beat Manchester United and Borussia Dortmund and Sevilla racked up notable victories.
Midtjylland pulled off the shock of the night, with Valencia – in record-equalling style – and Sevilla assuming notable round of 32 first-leg leads of their own.
United's troubles started before the match even kicked off when goalkeeper David de Gea was injured in the warm-up.
The Spain international failed to respond to treatment and was replaced in the team by Sergio Romero.
United were already without 12 players through injury or illness including captain Wayne Rooney.
de Gea has a knee problem so we have to wait and see. We will
investigate that with a scan," manager Louis Van Gaal said after the
match. "When you play with another team every week, with other players,
it doesn't help."