Naruto Uzumaki is a young boy who has the Nine-Tailed Demon Fox sealed within him. Twelve years before the start of the series, the Nine-Tailed Demon Fox attacked the ninja village Konohagakure, slaughtering many people. In response, the leader of Konohagakure and its ninja military – the Fourth Hokage – sacrificed his life to seal the demon inside Naruto when he was a newborn. Konohagakure, however, regarded Naruto as if he were the demon fox itself and mistreated him throughout most of his childhood. A decree made by the Third Hokage, who replaced the Fourth Hokage after his death, forbade anyone mention the attack of the demon fox to anyone. Years later, Naruto is tricked by the renegade ninja Mizuki into stealing a forbidden scroll, but is stopped by his teacher, Iruka Umino. When Iruka almost dies while protecting Naruto from Mizuki, Naruto defeats Mizuki using the power from the scroll, which develops the supernatural ability Jutsu Shadow Clone Technique that creates clones from himself. That encounter makes Naruto realize he was the container of the demon fox.

The main story follows Naruto and his friends' personal growth. Naruto befriends two comrades, Sasuke Uchiha and Sakura Haruno, who are assigned with him to form a three-person team named Team 7 under an experienced sensei named Kakashi Hatake. Like all the ninja teams from the every village, Team 7 is in charge in completing missions requested by villagers such as being bodyguards. During the course of the missions, Naruto also befriends other characters that he meets throughout the series. They learn new abilities, get to know each other and other villagers better, and experience a coming-of-age journey as Naruto dreams of becoming the Hokage of Konohagakure. After several missions, Kakashi allows Team 7 to participate into a ninja exam in which they can improve their ranks, and thus, be part of harder missions. During the exams, Orochimaru, a criminal at the top of Konohagakure's most wanted list, attacks Konoha killing the Third Hokage as an act of revenge. This causes one of the three legendary ninja, Jiraiya to search for his partner Tsunade, to become the Fifth Hokage. During that search, it is revealed that Orochimaru also desires to acquire Sasuke Uchiha due to his powerful genetic heritage. Believing Orochimaru will be able to give him the strength needed to kill his brother Itachi, who destroyed all his clan, Sasuke goes to him. Tsunade sends a group of ninja including Naruto to make Sasuke return to Konoha, but Naruto is unable to defeat him. Naruto does not give up on Sasuke, leaving Konoha for two-and-a-half years of training under Jiraiya's tuition to prepare himself for the next time he encounters Sasuke.

After the training period, a mysterious organization called Akatsuki attempts to capture the nine powerful tailed beasts including the Nine-Tailed Demon Fox sealed inside of Naruto. Several ninjas from Konohagakure, including Team 7, fight against the Akatsuki members and search for their teammate Sasuke. Although they manage to save the host from the One-tailed beast, Gaara, Akatsuki is successful in capturing seven of the creatures. Sasuke, in the meantime betrays Orochimaru and faces Itachi to take revenge. Although Itachi dies in battle, Sasuke is later told by the Akatsuki founder Madara Uchiha that Itachi was ordered by Konohagakure's leadership to destroy his clan. Saddened with the revelation, Sasuke joins forces with Akatsuki to destroy Konohagakure. Meanwhile, as several Akatsuki members are defeated by the Konohagakure ninja, the leader, Pain, invades the village to capture Naruto. However, Naruto defeats all of Pain's bodies and convinces the real one to leave. With Pain having left Akatsuki, Madara announces that he wants to obtain the nine tailed beasts in order to perform an illusion powerful enough to control humanity. As all the ninja villages' leaders refuse to aid him, they join forces to confront him.