Nichijou primarily focuses on the daily antics of a trio of childhood friends—high school girls Mio Naganohara, Yuuko Aioi and Mai Minakami—whose stories soon intertwine with the young genius Hakase Shinonome, her robot caretaker Nano, and their talking cat Sakamoto. With every passing day, the lives of these six, as well as of the many people around them, experience both the calms of normal life and the insanity of the absurd. Walking to school, being bitten by a talking crow, spending time with friends, and watching the principal suplex a deer: they are all in a day's work in the extraordinary everyday lives of those in Nichijou.

Guts, a man who will one day be known as the Black Swordsman, is a young traveling mercenary characterized by the large greatsword he carries. He accepts jobs that offer the most money, but he never stays with one group for long—until he encounters the Band of the Falcon. Ambushed after completing a job, Guts crushes many of its members in combat. Griffith, The Band of the Falcon's leader and founder, takes an interest in Guts and duels him. While the others are no match for Guts, Griffith defeats him in one blow. Incapacitated and taken into the Band of the Falcon's camp to recover, Guts wakes up two days later. He confronts Griffith, and the two duel yet again, only this time with a condition: Guts will join the Band of the Falcon if he loses. Due to his fresh injuries, Guts loses the fight and is inducted by Griffith. In three years' time, Guts has become one of the Band of the Falcon's commanders. On the battlefield, his combat prowess is second only to Griffith as he takes on large groups of enemies all on his own. With Guts' immense strength and Griffith's leadership, the Band of the Falcon dominate every battle they partake in. But something menacing lurks in the shadows, threatening to change Guts' life forever.

Staz Charlie Blood is a powerful vampire who rules the Eastern district of Demon World. According to rumors, he is a bloodthirsty and merciless monster, but in reality, Staz is just an otaku obsessed with Japanese culture and completely uninterested in human blood. Leaving the management of his territory to his underlings, Staz spends his days lazing around, indulging in anime, manga, and games. When Fuyumi Yanagi, a Japanese girl, accidentally wanders through a portal leading into the demon world, Staz is overjoyed. But just as he is starting to feel an unusual attraction to her, his territory is attacked, resulting in Fuyumi's untimely death. She turns into a wandering ghost and the crestfallen Staz vows to resurrect her as this would mean being able to travel to the human world, something he has always dreamed of. Blood Lad follows Staz and Fuyumi, soon joined by the spatial magician Bell and the half-werewolf Wolf, as they travel to find a magic that can bring humans back to life.

Katsuhira Agata is a quiet and reserved teenage boy whose sense of pain has all but vanished. His friend, Chidori Takashiro, can only faintly remember the days before Katsuhira had undergone this profound change. Now, his muffled and complacent demeanor make Katsuhira a constant target for bullies, who exploit him for egregious sums of money. But their fists only just manage to make him blink, as even emotions are far from his grasp. However, one day Katsuhira, Chidori, and four other teenagers are abducted and forced to join the Kizuna System as official Kiznaivers. Those taking part are connected through pain: if one member is injured, the others will feel an equal amount of agony. These individuals must become the lab rats and scapegoats of an incomplete system designed with world peace in mind. With their fates literally intertwined, the Kiznaivers must expose their true selves to each other, or risk failing much more than just the Kizuna System.