The Reborn! story revolves around a boy named Tsunayoshi "Tsuna" Sawada, who is chosen to become the Vongola Family's boss due to him being the great-great-great-great grandson of the first Vongola boss, who had moved to Japan from Italy during his time. He is told by Reborn that he will become the tenth (Italian decimo) Vongola boss. Also, the other candidates for the position of the head of the Vongola Family have died. For these reasons, Tsuna is the only remaining heir. As such, Timoteo a.k.a. "Vongola IX", the current head of the family, sends Reborn, an infant hitman from Italy, to train Tsuna. Tsuna then unwillingly undergoes training from Reborn. Reborn's main method of teaching Tsuna is the "Dying Will Bullet", which will make the person be "reborn" with a stronger self intent on fulfilling his dying will. Through his experiences, the initially clumsy and underachieving Tsuna unconsciously becomes stronger and more confident, which ultimately makes him better suited as the Vongola Family's boss despite continuing to reject his Mafia inheritance. He also starts making several friendships such as his crush Kyoko Sasagawa.
Tsuna goes through many predicaments in his progress of becoming the Vongola boss including fighting against escaped Mafia convicts posing as Kokuyo Junior High students. Later, The Varia, Vongola assassin squad, claim the right for their boss, Xanxus to be the true Vongola boss, and start a competition to decide it. To defeat the Varia, Reborn recruits most of Tsuna's schoolmates to become the Vongola guardians: Hayato Gokudera, a dynamite expert who wishes to be his right-hand man, Takeshi Yamamoto, a baseball player who thinks the Mafia is a game, Ryohei Sasagawa, the energetic captain of the school boxing club, and Kyoya Hibari, the deadly head prefect. Lambo, a weak infant assassin who came to kill Reborn, and Chrome Dokuro, a girl who has a mental and physical link with the criminal Mukuro Rokudo, joins them as well. Later, after defeating the Varia, Tsuna and his friends are transported to the future where they must face the Millefiore Family, who are annihilating the Vongola. As Tsuna and the Vongola Guardians from his time fight the Millefiore they learn that Shoichi Irie, a comrade of Tsuna's future self, was the one who sent them to the future as the future Tsuna said they were the only ones who can defeat the Millefiore leader Byakuran. It is later revealed that Byakuran has gained knowledge from parallel worlds and that he wants to obtain all the Mafia rings in order to obtain a power similar to omniscience.
After defeating Byakuran, Tsuna and co return to the present where they learn that Tsuna is to undergo the inheritance ceremony to become the new leader of the Vongola family. However, the ceremony is attacked by the Shimon Family, who have sworn revenge on Vongola Primo for supposedly betraying the first Shimon boss. Using the power of the Shimon rings, they have destroyed the Vongola Rings, left Yamamoto hospitalised and kidnapped Chrome. However, a man named Talbot reconstructs the Vongola Rings into the Vongola Gear, and Tsuna and the remaining guardians go to Shimon's hideout where they must face the Shimon family in battles with their prides on the line.