The antagonists of the Reborn! anime and manga series, known in Japan as Katekyō Hitman Reborn!, are created by Akira Amano. Set in a fictional town called Namimori in modern Japan, the series' main protagonists are of Japanese descent. However, their connection to an Italian Mafia family results in a majority of other characters introduced being mainly of Italian descent, including most of its antagonists.

The story centers on middle school student Tsunayoshi "Tsuna" Sawada, who finds out that he is the heir to the Vongola crime family. Reborn, the titular character and infant hitman, is sent to train him, and slowly recruits members into Tsuna's own Mafia family. They eventually attract attention from those who want to annihilate the future boss of the Vongola Family. Enemies such as the Kokuyo Gang, a group of Mafia criminals, and The Varia, an elite team of assassins, prove to be formidable challenges for Tsuna and his comrades. When some of the characters are later transported into an alternate future, nine years and ten months later, they have to adapt to a world where every Vongola member, as well as their allies, is being hunted down by a powerful rival family, the Millefiore. After returning from the future, they have to fight against an allied Family of Vongola since first generation who's seeking revenge to Vongola, Simon Family who turned out to be manipulated by Vongola Primo's Mist Guardian, Demon Spade who intended to rebuild the Vongola that he desire. Later, Tsuna and the others participate in Representative Battle of the Rainbow under request from the Arcobaleno with the winner will be able to have his or her curse removed. However, things started to get worse once an Arcobaleno with a clear pacifier, Bermuda von Veckenschtein appears with his team and participate the Representative Battle in order to get his revenge on Checker Face at the cost of the Arcobaleno's lives.

The Kokuyo Gang is a group led by Mukuro Rokudo, who formed the group after escaping from a special, high security jail in Italy which housed heinous criminals who have even committed crimes against the Mafia. Along with the two comrades he escaped with, Ken Joshima and Chikusa Kakimoto, he recruited other Mafia criminals who were able to break out from the same jail some time later. After their defeat at the hands of Tsuna and his friends, they were all once again imprisoned, though Chikusa and Ken are later able to escape, while Mukuro strikes a deal with the Vongola for their safety.

Mukuro Rokudo (六道 骸, Rokudō Mukuro) is a 15-year-old Mafia criminal who escaped from an Italian prison, which held some of the most dangerous Mafia criminals, before he was to be executed. Not long after, he, along with his two subordinates, came to Japan, enrolled in Kokuyo Junior High, and started the Kokuyo Gang, which consists of heinous criminals who have recently escaped from prison. Skilled in casting illusions as well as mind control, he attempts to take his revenge on the Mafia by taking over Tsuna's body and using him to wreak havoc. When his plan fails due to Tsuna's interference, he is once again imprisoned. However, later on in the series, after possessing the body of Chrome Dokuro, he takes on a more supportive role for the series' main characters, though still prefers to not associate with them. He is voiced by Toshinobu Iida in the anime.

Ken Joshima (城島 犬, Jōshima Ken) is a 14-year-old loyal friend and follower of Mukuro. Born on July 28, he was also experimented on by the Estraneo Family, and decided to follow Mukuro when the boy killed their captors. The experimentation on him resulted in his ability to gain the attributes of certain animals, like wolves and lions, when he changes to different sets of teeth, increasing his agility, strength, and senses. He was Chikusa's cellmate in jail and often calls him "Kakipi". He is defeated by Takeshi Yamamoto and later defeated once again by an injured Kyoya Hibari. He is taken away by the Vendicare, but later escapes. Ken returns for the Vongola Tournament, serving as a bodyguard for Chrome Dokuro, whom he is fond of despite he often mocks and berates. He is voiced by Ryō Naitō in the anime.

Chikusa Kakimoto (柿本 千種, Kakimoto Chikusa) is a 14-year-old loyal friend and follower of Mukuro. Born on October 26, he, along with Mukuro and Ken, was experimented on by the Estraneo Family, and accepted Mukuro's offer to come with him when the latter killed their captors. He uses a pair of metal yo-yos that shoot poisonous needles as his primary weapons. After arriving in Namimori, he loses a battle against Hayato Gokudera, though finds out the identity of the tenth Vongola boss. Later, after sustaining further injuries by Kyoya Hibari, he is taken away and imprisoned by the Mafia's guardians, the Vendicare, along with the rest of the gang. He and Ken are able to successfully escape, with Mukuro ensuring their safety by striking a deal with Iemitsu Sawada. He returns for the Vongola Tournament, serving as a bodyguard for Chrome Dokuro, whose well-being is of concern to both him and Ken despite his open dislike for her. He is voiced by Toshiyuki Toyonaga in the anime.

Chrome Dokuro is a loyal 13-year-old vessel of Mukuro and one of the newest members of the gang. She is originally a girl named Nagi who was found by Mukuro when on the verge of death after her attempt to rescue a cat from traffic accident at the cost of her right eye and several of her organs. Mukuro allowed her to live by creating illusionary organs for her with his illusion, intertwining their existence. She became co-Mist Guardian of Vongola, fighting against Mammon in the Ring Conflict, which result on her lost until Mukuro switched place with her and defeats Mammon. A week after Mukuro's release from Vendicare prison, she was kicked out from the gang by Mukuro and begins living on her own in Namimori with Tsuna and his friends. The reason of her discard was revealed during the third day of Representative Battle; it was because of her own dilemma between wanting to be acknowledged as individual and wanting to keep living with Mukuro's illusionary organs, causing her health deteriorating. This left Mukuro no choice but to keep her at distance from him. However, she's able to overcome her dilemma and recreate her organs with her own power, defeating two Vindices with hers and Mukuro's combined power. As she and Mukuro shared one body, she's able to use two of Mukuro's six skills. However, once Mukuro was freed from Vendicare Prison, she can no longer use this ability. She used to use the same trident like Mukuro as her main weapon, but after Mukuro was released, the spikes of her trident reduced to one. She is voiced by Satomi Akesaka in the Anime.

M.M. (エム・エム, Emu Emu) is a 15-year-old Mafia criminal who broke out of prison after Mukuro escaped. Born on July 3. She believes that money is the most important thing. After her defeat at the hands of Bianchi, she is later taken away by the Vendicare, but later rejoined the gang after Mukuro is released from prison. Her weapon is a clarinet that is constructed like a microwave oven. When played, the clarinet creates special sound waves that cause atoms to vibrate at an incredible rate which results in the substance the clarinet is aimed at to boil instantly. She calls the attack Burning Vibrato. When in close range combat, her clarinet splits, becoming a pair of nunchaku. She is voiced by Shōko Ishii in the anime.