Ten years after the Ceremonial Battle, a teenage boy named Judai Yuuki (Jaden Yuki) heads off in order to join the Duel Academia (Duel Academy) located on a remote island off the coast of Japan. There he meets his fellow students and gains a few friends, along with a few enemies. Judai is put into the lowest rank of Osiris Red (Slifer Red), but he continues to test his skills against the students and faculty to prove his worth as a Duelist and earn the respect of everyone around him.

The plot of the series revolves around three youkai, Bem, Bera and Barro, who arrive at a large coastal city and come across an evil atmosphere, which was brought about by immoral behavior by humans and mischief caused by monsters and youkai. They therefore decide to stay in the city, fighting against other monsters and yōkai which attack humans, making a few friends in the way. Even though the three youkai are often abused by other human beings due to their appearance, they still strive in protecting the human populace of the city from other monsters, one day hoping to become human beings in return for their good actions.