Dr. Kenzou Tenma, an elite neurosurgeon recently engaged to his hospital director's daughter, is well on his way to ascending the hospital hierarchy. That is until one night, a seemingly small event changes Dr. Tenma's life forever. While preparing to perform surgery on someone, he gets a call from the hospital director telling him to switch patients and instead perform life-saving brain surgery on a famous performer. His fellow doctors, fiancée, and the hospital director applaud his accomplishment; but because of the switch, a poor immigrant worker is dead, causing Dr. Tenma to have a crisis of conscience. So when a similar situation arises, Dr. Tenma stands his ground and chooses to perform surgery on the young boy Johan Liebert instead of the town's mayor. Unfortunately, this choice leads to serious ramifications for Dr. Tenma—losing his social standing being one of them. However, with the mysterious death of the director and two other doctors, Dr. Tenma's position is restored. With no evidence to convict him, he is released and goes on to attain the position of hospital director. Nine years later when Dr. Tenma saves the life of a criminal, his past comes back to haunt him—once again, he comes face to face with the monster he operated on. He must now embark on a quest of pursuit to make amends for the havoc spread by the one he saved.

Edo is a city that was home to the vigor and ambition of samurai across the country. However, following feudal Japan's surrender to powerful aliens known as the Amanto, those aspirations now seem unachievable. With the once-influential shogunate rebuilt as a puppet government, a new law is passed that promptly prohibits all swords in public. Enter Gintoki Sakata, an eccentric silver-haired man who always carries around a wooden sword and maintains his stature as a samurai despite the ban. As the founder of Yorozuya, a small business for odd jobs, Gintoki often embarks on endeavors to help other people—though usually in rather strange and unforeseen ways. Assisted by Shinpachi Shimura, a boy with glasses supposedly learning the way of the samurai; Kagura, a tomboyish girl with superhuman strength and an endless appetite; and Sadaharu, their giant pet dog who loves biting on people's heads, the Yorozuya encounter anything from alien royalty to scuffles with local gangs in the ever-changing world of Edo.

Sentenced to death, ninja Gabimaru the Hollow finds himself apathetic. After leading a blood-soaked life, Gabimaru believes he deserves to die. However, every attempt to execute him inexplicably fails. Finally, Sagiri Yamada Asaemon, a fledgling member of a famed executioner clan, is asked to take Gabimaru's life; yet Sagiri makes no move to kill him as requested. Insisting that Gabimaru will not die because of his love for his wife, Sagiri instead offers him the chance to obtain a full pardon for his crimes. If he can travel to the island of Shinsekyo and obtain the Elixir of Life—which supposedly grants immortality—and bring it back for the shogun, then his freedom will be assured. But of the many who have traveled to Shinsekyo in search of the mythical Elixir, not a single person has returned sound of mind, if at all. Though unaware of the numerous dangers ahead, Gabimaru decides to accept the offer—alongside ten other death row convicts—in hope that he and his wife may finally live in peace.

During the early 1930s in Chicago, the transcontinental train, Flying Pussyfoot, is starting its legendary journey that will leave a trail of blood all over the country. At the same time in New York, the ambitious scientist Szilard and his unwilling aide Ennis are looking for missing bottles of the immortality elixir. In addition, a war between the mafia groups is getting worse. On board the Advena Avis, in 1711, alchemists are about to learn the price of immortality. Based on the award-winning light novels of the same name, Baccano! follows several events that initially seem unrelated, both in time and place, but are part of a much bigger story—one of alchemy, survival, and immortality. Merging these events together are the kindhearted would-be thieves, Isaac and Miria, connecting various people, all of them with their own hidden ambitions and agendas, and creating lifelong bonds and consequences for everyone involved.