The anime deliberately took a rom-com direction far removed from the original manga, with the director explaining that he wanted to draw inspiration without hesitation from the romantic comedies of the Weekly Shōnen Jump of old, even accepting a somewhat corny side.

Unlike the manga which contains bloody scenes, the anime eliminates them entirely in favor of slapstick humor and fan-service scenes, notably a number of panty shots far higher than in the original work.

While the first season is based on the first five volumes of the manga, many elements are modified: several characters no longer have the same motivations, certain antagonists from the manga (such as Ishigami) completely disappear from the animated plot, and key scenes are replaced by original versions (such as the final battle against Kuyō, won by Inner Moka rather than Tsukune transformed into a vampire).

The second season, titled CAPU2, is almost entirely composed of original stories invented for the anime rather than direct adaptations of the manga.

The original soundtrack frequently uses covers of idol songs from the 1980s as background music, and an entire album, "Rosario+Vampire IDOL COVER BEST", brings together these covers performed by the seiyū of the female characters.

During the broadcast of the second episode of the first season on tvk channel on January 11, 2008, a failure of the master broadcast tape caused a broadcast incident (disturbed image), which led to a rebroadcast of the episode on January 16 of the same year.

Some local stations such as TV Osaka or TV Aichi censored scenes deemed too suggestive on air by masking them with the image of a mysterious bat (nazo kōmori), a censorship reinforced for season 2 where TV Osaka even added bear patterns in addition to the bat on most of the scenes in question.

For the opening animation of the second season, the movements of professional dancers executing the theme music choreography were captured by motion capture, then the animators drew the characters over this movement data.

The castings of the two dramatic CDs released before the anime (2006 and 2007) were directly taken over for the television series, with the exception of the actor of Tsukune Aono who went from Daisuke Kishio (written differently in kanji) to another performer for the anime.