Throughout history, humans have been at odds with Beastmen—a species capable of changing shape due to their genetic Beast Factor. Because of this conflict, Beastmen have been forced into hiding. Anima City serves as a safe haven for these oppressed individuals to live free from human interference. During a festival celebrating the town's 10th anniversary, Michiru Kagemori, a human who suddenly turned into a tanuki, finds that Anima City is a far cry from paradise. After witnessing an explosion in the square, she is confronted by Shirou Ogami, a seemingly indestructible wolf and sworn protector of all Beastmen. As they pursue the criminals behind the bombing, the two discover that Michiru is anything but an ordinary Beastman, and look to investigate her mysterious past and uncanny abilities. Could she turn out to be the missing link between Humans and Beastmen?

In the mysterious future, crystalline organisms called Gems inhabit a world that has been destroyed by six meteors. Each Gem is assigned a role in order to fight against the Lunarians, a species who attacks them in order to shatter their bodies and use them as decorations. Phosphophyllite, also known as Phos, is a young and fragile Gem who dreams of helping their friends in the war effort. Instead, they are told to compile an encyclopedia because of their delicate condition. After begrudgingly embarking on this task, Phos meets Cinnabar, an intelligent gem who has been relegated to patrolling the isolated island at night because of the corrosive poison their body creates. After seeing how unhappy Cinnabar is, Phos decides to find a role that both of the rejected Gems can enjoy. Houseki no Kuni follows Phos' efforts to be useful and protect their fellow Gems.

Years ago, astronaut Byakuya left behind precious materials in the belief that his son, the scientifically-gifted Senkuu, would one day find them. In the present, the Kingdom of Science's Kohaku and Ginrou have infiltrated the harem of the Petrification Kingdom’s leader with the help of Amaryllis, a local girl. At first, their mission progresses without a hitch. Unfortunately, an error enacted by Kohaku and Ginrou leads Minister Ibara and the Island’s strongest warrior, Moz, to identify the intruding duo as enemies. Even worse, Moz tails Amaryllis when she returns to inform Senkuu of the news, discovering the scientist's secret hideout. However, Moz's agenda does not align with Ibara's—he wants to dethrone the minister and keep the petrification device for himself. If Senkuu plays his cards right, he could gain a powerful ally and win the war once and for all.

The war between the Terrans and the Vers Empire of Mars has ended, allowing humanity to blissfully enjoy their lives in a time of peace. Nineteen months later, however, the Vers princess makes a shocking public declaration: the Terrans are a foolish race that covets resources, destroys nature, and are devoted to the pursuit of pleasure. And so, to protect their precious Earth, she calls upon her knights to take up arms, and the raging battle between the two civilizations reignites. Slaine Troyard has found a place among the Martians, giving Earth a short respite from the war against the Vers Empire. However, a peaceful resolution seems inconceivable. The various people who fought desperately for survival in the past now find themselves in the midst of yet another bloody and chaotic conflict, one that will forever alter the fate of humankind.