Opening with a teenaged Boruto Uzumaki facing a foe named Kawaki during the destruction of his village, the manga follows with a retelling of events in Boruto: Naruto the Movie with added content.^[2] The son of the Seventh Hokage Naruto Uzumaki, Boruto feels angry over his father placing the village before his family. At that time, Boruto becomes a member of a ninja team led by Naruto's protégé Konohamaru Sarutobi, alongside Sarada Uchiha, the daughter of Sasuke and Sakura Uchiha, and Mitsuki, Orochimaru's artificial son. Sasuke returns to the village to warn Naruto of an impending threat relating to deduce the motivations of Kaguya Ōtsutsuki. Boruto asks Sasuke to train him for the upcoming Chunin exam to impress his father.

During the exam, Momoshiki and Kinshiki Ōtsutsuki, the duo whom Sasuke met, abduct Naruto so they can use Kurama, a tailed beast sealed inside his body, to revitalize the dying Divine Tree from the dimension they came from. Boruto, Sasuke and the four Kages, the leaders of other ninja villages, set out to rescue Naruto. The battle ends when Momoshiki, sacrificing Kinshiki to increase his own strength, is defeated by Boruto and Naruto with Sasuke's help; Momoshiki survives long enough to realize Boruto's full potential while warning him of future tribulations. After recovering from his fight, Boruto decides to become like Sasuke in the future, while entrusting Sarada to follow her dream of becoming the next Hokage.

On a next mission, Boruto serves as a bodyguard for the Fire Daimyo's son Tento, with the two finding kinship in both wanting to be acknowledged by their fathers. When a group of bandits known as the Mujina kidnaps Tento, Boruto saves him with the group's leader incarcerated due to having knowledge on the mark that Momoshiki placed on Boruto. Naruto and the other learn there is a group called "Kara" (殻, lit. The Husk) searching for people with the marks called Karma. Boruto's team meets Kara's fugitive Kawaki, a boy who also has Karma. Kawaki becomes an adopted member of the Uzumaki family to protect him. However, when trying to protect Kawaki, Naruto and Sasuke are defeated by the leader of Kara, Jigen, who seals Naruto away while Sasuke escapes. Team 7 saves Naruto when Boruto's Karma causes him to be possessed by Momoshiki.

After learning of this, Sasuke discovers all Karma users will be taken over by the Ōtsutsuki clan, including Jigen. Meanwhile, a mutiny starts to form in Kara, with Koji Kashin challenging Jigen, while Amado goes to Konoha to seek asylum in exchange for information, revealing the real leader of Kara as Isshiki, who has been possessing Jigen ever since he was betrayed by Kaguya when they came to Earth millennia ago, and that Karma allows the Ōtsutsuki clan to resurrect via the host's body. Although Koji kills Jigen, forcing Isshiki to reincarnate imperfectly while Kawaki's Karma is removed in the process, Isshiki forces Koji to retreat and leaves to attack Konoha.

There, Isshiki searches for Kawaki. Naruto faces him head-on, preparing to fight. Boruto transports himself and Isshiki to another place away from the village with Sasuke and Naruto following. Since Boruto is Momoshiki's vessel, Isshiki plans to feed him to his Ten Tails in order to plant a Divine Tree. With Naruto's new power, the Baryon Mode, he defeats Isshiki before Kawaki tricks him, causing Isshiki to die, but at the cost of Kurama's life. Boruto, possessed by Momoshiki, stabs out Sasuke's Rinnegan. However, Sasuke and Kawaki face Momoshiki until Boruto recovers his body. After being defeated, Isshiki requests Code, who was guarding the Ten-Tails, to carry on Ōtsutsuki's will by sacrificing either Boruto or Kawaki to the Ten-Tails, and eat the chakra fruit, and become Ōtsutsuki himself.

Code vows to avenge Isshiki, by pursuing Naruto, Sasuke, Kawaki and Boruto. He visits Boro's hideout and effortlessly kills the guards. He then proceeds to release one of the strongest cyborgs created by Amado that was supposed to have been disposed off. The female cyborg Eida agrees to help Code kill Naruto if he in turn spares Kawaki for her to have a normal romance with, because her powers of seduction hinders her from experiencing proper love. Since her powers do not work on Ōtsutsuki, and Kawaki and Boruto are already part of them, she can experience it with them.