The story takes place in Japan. The year is 2030 and Earth has been completely overrun by a viral disease named Gibia that turns infected people into various different monsters, based on their age, sex, and race. A samurai and a ninja from the early Edo period travel together through time and arrive in a ruined Japan to aid a professor working on a cure for the virus. Together, they fight countless Gibia monsters, outlaws, and other fierce foes on their journey to save mankind.

The Sengoku era gave birth to many historical legends. One of them is Naoe Kanetsugu, the brilliant military general of the Uesugi family. Together with Maeda Keiji, a legendary warrior on the battlefield, who become lifelong friends with each other, they carve out a piece of history in the most dangerous and volatile time in Japan's history. The two men recall their beginnings and the journey they took to get to the accomplished position they now sit at.

Following the temporary retreat of the Altana Liberation Army from the Kabuki District, the state of the war has seemingly improved. However, as the Oniwaban, Shinsengumi, and residents of the district combat the army's remnants, Edo's greatest inventor Gengai Hiraga is abducted. Responsible for causing the enemy's withdrawal by rendering their weapons useless, Gengai's nanomachine virus is now at risk of being shut down. Meanwhile, a laser capable of obliterating a planet is activated in Earth's orbit on the Liberation Army's mother ship. Another battle ensues when Shinsuke Takasugi and the rest of the Kiheitai arrive on the vessel to stop the weapon from firing. Forced to fight a war on two fronts, the Yorozuya and their allies must prevail on both sides to save Edo and the rest of the world.

After the fierce battle on Rakuyou, the untold past and true goal of the immortal Naraku leader, Utsuro, are finally revealed. By corrupting the Altana reserves of several planets, Utsuro has successfully triggered the intervention of the Tendoshuu’s greatest enemy: the Altana Liberation Army. With Earth as the main battleground in this interplanetary war, Utsuro's master plan to destroy the planet—and himself—is nearly complete. An attack on the O-Edo Central Terminal marks the beginning of the final battle to take back the land of the samurai. With the Yorozuya nowhere in sight, the bakufu all but collapsed, and the Shogun missing, the people are left completely helpless as the Liberation Army begins pillaging Edo in the name of freeing them from the Tendoshuu's rule. Caught in the crossfire between two equally imposing forces, can Gintoki, Kagura, Shinpachi, and the former students of Shouyou Yoshida put aside their differences and unite their allies to protect what they hold dear?