The Spaniards went 1-0 up through Antonio Barragan after five minutes but looked in trouble when Seydou Keita was sent off in the 25th and gave away a penalty in the process.
Diego Alves kept out Roman Bezjak's spot-kick, though, and the visitors went on to add more goals through Federico Cartabia and Philippe Senderos.
Stunned Ludogrets then had a man of their own sent off, Juninho Quixada, to cap a miserable night.
The writing was on the wall for them early on as Barragan finished off Paco Alcacer's ball with a sweet finish to put Valencia ahead.
Mihail Aleksandrov led the home response with an effort that went wide, before Barragan spooned over when he could have made it two.
Ludogrets then got their chance as Keita hauled down a clean-through Bezjak, leading to a red card, but Alves made a fine save from the same player's penalty.
They had another close shave after that as Virgil Misidjan crunched a shot into post, and they were made to pay for their misses as Alcacer dinked a ball into the box, right onto the boot of Cartabia who volleyed in a brilliant second.
Alves again kept Valencia in it after that, denying Marcelinho from close range, and then Senderos finished things off.
Jeremy Mathieu's cross caused havoc in the box and the former Arsenal man got the final touch at the back post with 59 minutes on the clock.
After that all that was left was for Quixada to get his marching orders for a foul on Joao Pereira.