Pizzi's men eased to a 3-0 first leg win in Sofia last week, despite playing most of the match with 10 men after the 24th-minute sending-off of Seydou Keita.
Yet despite the virtual certainty of progression to the quarter-finals, Pizzi has called on his players to take the job seriously at the Mestalla on Thursday - and for the club's fans to turn out to urge them on.
Pizzi said: "We must not underestimate our opponents and there is no difference in how we are approaching the game.
"We must not make the mistake of thinking the match is over. Sometimes when a team comes with nothing to lose there can be trouble. This is why it is important the public come and support us."
Valencia's win in Bulgaria was in stark contrast to their domestic form, with Sunday's 1-0 loss at Real Sociedad representing their third successive Primera Liga match without a win.
Pizzi has an injury doubt over defender Philippe Senderos, who scored the third goal in Sofia, while Ricardo Costa is definitely out.
Ludogorets boss Stoicho Stoev faces a selection crisis in the wake of a battling domestic cup win over rivals Lovech last Sunday.
Stoev could be without Cosmin Moti, Choco and Dani Abalo for the trip to Spain, while Fabio Espinho is suspended.