In an alternate version of Japan's Edo period, the sky was suddenly filled with alien spaceships. These extraterrestrials, known as the Amanto, invaded Earth and quickly seized control of the government. The shogunate was reduced to a puppet regime, and a new law was passed that banned the carrying of swords in public, effectively ending the era of the samurai. The story takes place roughly twenty years after this invasion, where the city of Edo has become a chaotic blend of traditional Japanese architecture, futuristic technology brought by the aliens, and bizarre extraterrestrial beings living alongside humans.

At the heart of the series is Gintoki Sakata, a lazy, eccentric, and perpetually broke silver-haired samurai who still carries a wooden sword and stubbornly clings to his warrior spirit. He runs a small business called the Yorozuya, which translates to "odd jobs" or "we can do anything," out of a rundown second-floor apartment. His two main employees are Shinpachi Shimura, a kind-hearted and glasses-wearing teenager who often acts as the straight man to Gintoki's antics while trying to uphold the honor of his family's dojo, and Kagura, a seemingly cute young girl who is actually a member of the physically powerful Yato alien clan, possessing superhuman strength and an endless appetite. They are often accompanied by Sadaharu, their giant white pet dog who is the size of a horse and has a habit of biting people's heads.

The narrative of Gintama is primarily episodic and focuses on the trio as they take on a wide variety of strange, dangerous, or just plain ridiculous requests from the citizens of Edo to pay their rent. Their clients range from alien royalty to local gangsters, and their jobs often lead to chaotic encounters with other major figures in the city. These include the Shinsengumi, a group of samurai who now serve as a special police force for the puppet government. Despite their official duties, the Shinsengumi members are a collection of oddballs themselves, including the stalker-like commander Isao Kondo, the mayonnaise-obsessed vice-commander Toshiro Hijikata, and the sadistic prodigy Sougo Okita. Other recurring characters include Kotaro Katsura, a former comrade of Gintoki from a past war who is now a wanted terrorist leader trying to overthrow the aliens, and his strange pet "Elizabeth," an anthropomorphic duck-like creature.

While the show is famous for its relentless comedy, meta-humor, and parodies of other anime and pop culture, it also contains several notable serious action arcs that advance an overarching plot. One of the earliest and most important of these is the Benizakura Arc, which introduces Gintoki's former friend-turned-mortal enemy, Shinsuke Takasugi, a ruthless revolutionary leading a terrorist group called the Kiheitai with the goal of destroying the corrupt world the samurai failed to protect. The Yoshiwara in Flames Arc delves into the backstory of Kagura's brother, Kamui, and introduces a powerful female ninja named Tsukuyo, who becomes a significant ally. Later, the Four Devas of Kabukicho Arc focuses on a turf war in the entertainment district that threatens Gintoki's friends and neighbors, exploring themes of family and belonging.

As the series progresses, these dramatic storylines become more frequent and interconnected. The Shogun Assassination Arc marks a major turning point, plunging the country into political chaos and revealing the truth about Gintoki's past and his relationship with his former teacher, Yoshida Shouyou. This leads directly into the Farewell, Shinsengumi Arc, which explores the dissolution of the Shinsengumi and the fates of its members. The final saga of the anime adapts the Silver Soul Arc, a massive, multi-part conclusion where the Yorozuya and all their former allies and enemies must unite to face an immortal, world-destroying entity named Utsuro, who is the dark origin of their beloved master. The series concludes after a long and brutal final battle that decides the fate of the land of the samurai.