Cardfight!! Vanguard features a world where the game Cardfight!! Vanguard is becoming the latest craze among trading card games, becoming a part of everyday life for people all over the world. The game is not limited to Earth alone; battles between the creatures used by the players take place on another planet called Cray. The story begins with Aichi Sendou, a timid middle schooler whose meek attitude often leaves him a target for bullies. Aichi was given a very rare card, "Blaster Blade", when he was very young. It's his one treasure that gives him hope. That is, until it gets taken from him. Although Aichi has never played Cardfight!! Vanguard before, he challenges the thief to a game in order to win the "Blaster Blade" back. This high-stakes game quickly draws Aichi into the world of Vanguard battles, which will test and change his worth as both a player and a person.

While the perfect getaway for most girls her age might be a fancy vacation with their loved ones, Rin Shima's ideal way of spending her days off is camping alone at the base of Mount Fuji. From pitching her tent to gathering firewood, she has always done everything by herself, and has no plans of leaving her little solitary world. However, what starts off as one of Rin's usual camping sessions somehow ends up as a surprise get-together for two when the lost Nadeshiko Kagamihara is forced to take refuge at her campsite. Originally intending to see the picturesque view of Mount Fuji for herself, Nadeshiko's plans are disrupted when she ends up falling asleep partway to her destination. Alone and with no other choice, she seeks help from the only other person nearby. Despite their hasty introductions, the two girls nevertheless enjoy the chilly night together, eating ramen and conversing while the campfire keeps them warm. And even after Nadeshiko's sister finally picks her up later that night, both girls silently ponder the possibility of another camping trip together.

Rikuo Uozumi has all but resigned himself to a bleak future, aimlessly working at a convenience store in Tokyo after graduating from college. His monotonous life is interrupted when the peculiar Haru Nonaka makes a lively appearance, frequently dropping by his workplace to befriend him. When Rikuo learns that an old college friend and crush, Shinako Morinome, has moved back into town, he reaches out to further their relationship. Unbeknownst to Rikuo however, Shinako is carrying painful memories from her past that were holding her back from accepting his feelings. Meanwhile, as Haru continually opens up to Rikuo, he discovers that she, much like him, is living by herself and wants to step out of her comfort zone into an uncertain future. The past lingers long in the mind, and the future remains elusive. At a crossroads along their intertwined paths, these three experience what it means to let go of their feelings of yesterday and embrace the change that tomorrow brings.

It is 1983, and Hinamizawa is under quarantine. A mysterious and deadly virus has been discovered within the small village, and its residents—such as teenager Keiichi Maebara and his friends Mion Sonozaki and Rena Ryuuguu—are left confused and frightened by the situation. As the villagers begin to search for a way to stop the affliction from spreading, some make drastic plans, which leaves Keiichi and his friends looking for a way to escape the village. But when tensions reach an all-time high, some of his group may not make it out unscathed as they fight for their lives against enemies both seen and unseen.