Former Liverpool youngster Antonio Barragan put Valencia into a fifth minute lead before the Spanish side saw Seydou Keita sent off on 25 minutes for conceding a penalty which was saved by Diego Alves.
Federico Cartabia increased Valencia's lead before half-time and ex-Arsenal and Fulham defender Philippe Senderos added a third goal just before the hour mark.
Ludogorets, who knocked out Lazio in the previous round, then had Juninho Quixada sent off late on to leave them with an uphill task to reach the quarter-finals.
The writing was on the wall for Ludogorets 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.
Ludogorets then got their chance as Keita hauled down a clean-through Roman 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 cracked a shot into a 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 Senderos, who joined Valencia from Fulham in January, 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.