The defending European champions were guaranteed top spot but completed a clean sweep for a second time in their history after goals from Cristiano Ronaldo, Gareth Bale, Alvaro Arbeloa and Alvaro Medran.
Ludogorets saw Marcelinho sent off midway through the first half and missed out on the Europa League as they struggled to contain the quality of the Spanish giants.
Amid early pressure from Real, Ludogorets' slim hopes of taking anything from the Santiago Bernabeu diminished with the loss of a man and a goal in quick succession.
Marcelinho – on target in the reverse fixture - handled Raphael Varane's goalbound header to earn a straight red card before Ronaldo converted the penalty to move past club legend Raul to outright second in the competition's record scorers list with his 72nd Champions League goal.
Bale doubled the advantage late in the first half with a header from Toni Kroos' corner before Arbeloa added a third 10 minutes from time with his first goal in over a year.
Young midfielder Medran added a touch of gloss to a straightforward outing with a late strike - his first at senior level - as Real eased to a 19th straight win in all competitions - breaking Barcelona's Spanish record for consecutive victories.
Having fallen behind early in the reverse fixture, Real were on the front foot from the off with Bale and Javier Hernandez threatening with headers in the opening stages.
Isco was thwarted by a smart Vladislav Stoyanov save 14 minutes in following Asier Illarramendi's clever ball before Virgil Misidjan tested Keylor Navas with a curled strike from the edge of the area.
However, Ludogorets were dealt a double blow 19 minutes in when Marcelinho was sent off for blocking Varane's header on the line with his hand.
Ronaldo made the visitors pay with a chipped effort from 12 yards to open the scoring and set Real on their way.
Ludogorets managed to keep Real at bay somewhat after the opener - displaying the defensive shape that had seen them lose just once in 11 games prior to Tuesday's clash.
However, the hosts' quality came to the fore again eight minutes before the break as Bale crashed a header off the crossbar and past Stoyanov to ease Real into the break two goals ahead.
Making the most of their numerical advantage, Real continued to threaten although visiting captain Svetoslav Dyakov went close before the hour as Navas was forced into an acrobatic stop.
With Georgi Dermendzhiev's men defending impressively and Real's victory under no real pressure, chances were at a premium until the latter stages.
Arbeloa - having already seen a header hit the crossbar - finished from close range before Medran's deflected strike looped over Stoyanov to give the 20-year-old his first goal for the club on his Champions League bow.
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