Saitama is an unemployed hero who has trained so hard that he has lost all his hair and gained overwhelming power, capable of defeating any opponent with a single punch. This strength, however, has become a source of boredom and existential frustration, as the thrill of battle has vanished entirely. The story is set on a continent whose cities face constant devastation from mysterious beings and monsters, questioning the sustainability of civilization.

Living in the abandoned and monster-infested Z-City, Saitama encounters Genos, a young cyborg seeking revenge against a rogue cyborg who killed his family. After witnessing Saitama effortlessly destroy a powerful mosquito-type monster, Genos becomes his self-appointed disciple, hoping to learn the secret of his strength. The secret, as Saitama explains, is a fairly routine but intense training regimen of 100 push-ups, 100 sit-ups, 100 squats, and a 10-kilometer run every day.

Seeking recognition, Saitama and Genos join the Hero Association, a bureaucratic organization founded by a wealthy businessman whose grandson was saved by a hero. While Genos aces the written exam and demonstrates immense power to earn a place in the elite S-Class, Saitama performs poorly on the written portion despite breaking all physical records, landing him in the lowest C-Class. This ranking system and the Association's questionable judgment become a recurring theme, as Saitama's power is often doubted and his accomplishments are sometimes credited to others or overlooked entirely.

The first major story arc introduces the House of Evolution, a research group creating powerful monsters. Saitama and Genos infiltrate their hideout, where Saitama easily defeats the group's ultimate creation, Asura Kabuto. Later, a giant meteor threatens to destroy Z-City. Despite the efforts of S-Class heroes like Genos and Metal Knight, Saitama is forced to destroy it, though the resulting fragments still cause significant damage to the city, for which he is unjustly blamed. During the Deep Sea King arc, a monster attacks a city during a rainstorm, defeating numerous heroes, including Genos. Saitama arrives and kills the creature with one blow, but to restore public faith in the other heroes who fought bravely, he allows them to take the credit.

The first season culminates with the arrival of Lord Boros and his Dark Matter Thieves, a group of alien conquerors who destroy City A. Boros, who has traveled across the universe seeking a worthy opponent, confronts Saitama aboard his massive spaceship. Their fight is the most prolonged in the series, with Boros surviving multiple hits and unleashing a devastating energy attack capable of scouring the planet's surface. Saitama finally ends the battle with a Serious Punch, whose shockwave kills Boros and destroys his ship.

The second season shifts focus to a new antagonist, Garou, the Hero Hunter. A former disciple of the martial arts master Bang (S-Class hero Silver Fang), Garou despises heroes and hunts them relentlessly, all while harboring a childhood dream of becoming a monster who brings fear to the world. Simultaneously, the Monster Association, a secret organization of powerful monsters, begins to abduct key figures, including the young boy Tareo. This leads to a large-scale conflict between the Hero Association and the Monster Association, with Garou caught in the middle, fighting both heroes and monsters as he edges closer to completing his monstrous transformation.