An apocalyptic event has ravaged Japan, leaving nothing but endless sandy plains behind, and a strange rusting disease terrorizes the remnants of civilization. According to the government, the horrific state of the new world is the result of mushroom spores being spread by the likes of Bisco Akaboshi, labeled the "Man-Eating Mushroom." But Bisco would beg to differ. In reality, he is a "Mushroom Protector," determined to uncover the legendary "Sabikui" mushroom—said to be the ultimate cure for the rusting disease. Joining him on his quest are his giant crab Akutagawa and the kind doctor Milo Nekoyanagi, who is actively searching for a rust poisoning treatment for his sick sister. Despite the prejudice aimed toward him by the common folk, Bisco refuses to give up on his quest to purify the rotting world.

Chise Hatori, a 15-year-old Japanese girl, was sold for five million pounds at an auction to a tall masked gentleman. Abandoned at a young age and ridiculed by her peers for her unconventional behavior, she was ready to give herself to any buyer if it meant having a place to go home to. In chains and on her way to an unknown fate, she hears whispers from robed men along her path, gossiping and complaining that such a buyer got his hands on a rare Sleigh Beggy. Ignoring the murmurs, the mysterious man leads the girl to a study, where he reveals himself to be Elias Ainsworth—a magus. After a brief confrontation and a bit of teleportation magic, the two open their eyes to Elias' picturesque cottage in rural England. Greeted by fairies and surrounded by weird and wonderful beings upon her arrival, these events mark the beginning of Chise's story as the apprentice and supposed bride of the ancient magus.

In the previous century, an unprecedented disaster known as the Invertia drastically reformed the world. The powers of existing nations declined significantly, paving the way for a conglomerate called the Integrated Empire Foundation to assume control. But more importantly, the Invertia led to the emergence of a new species of humans who are born with phenomenal physical capabilities—the Genestella. Its elite are hand-picked across the globe to attend the top six schools, and they duel amongst themselves in entertainment battles called Festas. Ayato Amagiri is a scholarship transfer student at the prestigious Seidoukan Academy, which has recently been suffering from declining performances. Through a series of events, he accidentally sees the popular Witch of Resplendent Flames, Julis-Alexia von Riessfeld, half-dressed! Enraged, Julis challenges him to a duel for intruding on her privacy. After said duel is voided by the student council president, Ayato reveals that he has no interest in Festas. Instead, he has enrolled in the academy to investigate the whereabouts of his missing elder sister. But when a more devious plot unravels, Ayato sets out to achieve victory, while being surrounded by some of the most talented Genestella on the planet.

Gakusen Toshi Asterisk 2nd Season continues the story of Genestella students Ayato Amagiri and Julis-Alexia von Riessfeld, who have progressed to the next round of the Phoenix Festa after a long and strenuous battle with sisters Irene and Priscilla Urzaiz. Despite Julis and Ayato's best attempts, the fact that Ayato's powers have been sealed is no longer a secret. Now at a major disadvantage, the duo must come up with a plan if they are to have any hope of winning the Phoenix Festa. Only one thing is for sure: the troubles heading their way are only going to get more insurmountable from here on.