Japanese Featherweight Champion Ippo Makunouchi has successfully defended and retained his title. Meanwhile, his rival, Ichirou Miyata, has resurfaced in Japan, aiming for his own Featherweight belt in the Oriental Pacific Boxing Federation. When the rest of the world comes knocking, however, will Japan's best fighters rise to the challenge and achieve glory at the top? Or will the small island nation be crushed under the weight of greater entities? This time, champions will become challengers issuing a call to the rest of the world and ready to show off their fighting spirit!

Mahiro Yasaka is just an ordinary high school student, until one day he is suddenly attacked by a dangerous monster. Just when everything seems to be lost, he is saved by a silver-haired girl named Nyaruko, who claims to be the shape-shifting deity Nyarlathotep from horror author H. P. Lovecraft's Cthulhu Mythos, sent by the Space Defense Agency to Earth. She explains to Mahiro that the creature chasing him was an alien called Nightgaunt, who had planned on abducting and selling him as a slave. After rescuing him from the alien, the Lovecraftian deity falls madly in love with Mahiro and forces herself into his household, much to his chagrin. Moreover, they are soon joined by two others from the fictional universe: Cthuko, a girl obsessed with Nyaruko, and Hasuta, a young boy easily mistaken for a beautiful female. Together, the three eccentric aliens protect Mahiro from the various extraterrestrial dangers that threaten both his and Earth's well-being, all the while making his life a living hell.

Right before the volleyball club's training camp in Tokyo, both Shouyou Hinata and Tobio Kageyama fail a final exam. As the make-up exams and the trip overlap, the boys plead their desperate case to the vice principal to no avail. Since their indispensable teammates are forced to stay behind to study, the club's members find different ways to help them pass and join the camp in time.

In his father's absence, teenager Ippo Makunouchi works hard to help his mother run her fishing boat rental business. Ippo's timid nature, his lack of sleep, and the sea smell make him an easy target for relentless bullies who leave him bruised and beaten on a daily basis. Mamoru Takamura, an up-and-coming boxer, rescues Ippo from a violent after-school incident and takes him back to the Kamogawa Boxing Gym for recovery. Takamura and his fellow boxers, Masaru Aoki and Tatsuya Kimura, are stunned by Ippo's powerful punches—a result of strong muscles developed through years serving his physically taxing family business. Following brief training under Takamura, Ippo impresses the other boxers in a practice match against prodigy Ichirou Miyata. He gains a rival in Miyata and a coach in Genji Kamogawa, the gym owner and a former boxer himself. As Ippo takes the first steps in his official boxing career, he faces off against a series of challenging opponents, each more powerful than the last. Victory, loss, and a cycle of dedicated training await Ippo on his journey to achieve greatness. With his tough body and unstoppable fighting spirit, the kind young man seeks to take on the world.