Juan Antonio Pizzi's men are in command of the last 16 tie heading into the second leg, following a 3-0 win over the Bulgarian outfit last Thursday in a game that saw both sides reduced to 10 men.
Seydou Keita was sent off for Valencia in the 24th minute, but Pizzi's side were still able to wrap up a comfortable victory as Federico Cartabia and Philippe Senderos added to Antonio Barragan's fifth-minute strike.
Forward Juninho Quixada was dismissed in the 80th minute for Ludogorets, who are now in need of a remarkable turnaround against a Valencia side in good form at home if they are to progress to the last eight.
The Spaniards have lost just one of their last 12 games in all competitions at the Mestalla and will be confident of keeping their hopes of winning the tournament alive.
Yet Valencia - who last won the competition in 2004 - do have their weaknesses.
Indeed, the win at Ludogorets in the opening leg was their first in four games and was immediately followed by a disappointing 1-0 La Liga defeat to Real Sociedad.
That setback left Valencia well adrift of the European spots in the Spanish top flight, and Pizzi's side will likely need to win the tournament in order to compete in it again next term.
Pizzi does not have any fresh injury worries to contend with, although a number of first-team players are still on the sidelines.
Keita is banned following his red card in Bulgaria, while captain Ricardo Costa is still unavailable with an ankle injury.
Winger Pablo Piatti (hamstring) and Oriol Romeu (knee) are yet to return to full fitness, but Jeremy Mathieu and Paco Alcacer are available after missing the loss to Sociedad through suspension.
Ludogorets will have to cope without Juninho following his indiscretion in the first leg, and midfielder Fabio Espinho is also banned.
The onus should be on top scorer Roman Bezjak to find the target and give the visitors hope after an outstanding season so far.
Bezjak has scored 17 goals in all competition this term, but crucially missed a penalty in the first leg after Keita had been given his marching orders for a clumsy foul on the Slovenian.
But even with Bezjak's presence victory appears highly improbable for Ludogorets against a team that Pizzi insists are determined to win the Europa League.
"We want to win the Europa League and we have a great advantage, more than we could have expected, but the tie isn't decided," Pizzi said.
"I don't call things until they're actually over. Our opponents will be driven to come back.
"We believe we can win this tournament and we'll try to show that in all our matches."
