PSV dominated the first half but were stunned after the break as Roman Bezjak and Virgil Misidjan both scored to secure victory for the visitors.
Marcelinho had the Bulgarians on the front foot straight away and fired just past the post in the second minute.
The Brazilian saw another shot go wide 12 minutes later before the Dutch side had their first real chance with Memphis Depay bringing a save out of Vladislav Stoyanov from 12 yards.
Depay put an effort wide just after the half-hour before PSV almost took the lead eight minutes before the break.
Tim Matavz saw his shot blocked behind and from the resulting corner Jeffrey Bruma put a header past the post.
PSV were dominating and Depay saw another shot saved but the deadlock was not broken before the break.
The visitors were the first to threaten in the second half with Dani Abalo seeing his shot parried by Jeroen Zoet before Junior Caicara blazed the loose ball over the bar.
And they had the lead on the hour as Bezjak's shot from distance found its way into the bottom corner.
Matavz then put a header wide from six yards and Ludogorets punished the hosts as Misidjan's shot hit the post but the Dutchman collected his own rebound and slotted home.
Depay put another shot wide with 10 minutes remaining but Phillip Cocu's men could not fight back as they fell to defeat.