The journey begins with Gon taking a series of bizarre tests to become a Hunter, which includes navigating a deadly jungle, hunting other applicants, killing a wild boar, an extraordinarily long underground marathon and making sushi. During the Hunter Exam, Gon meets and befriends three of the applicants, Kurapika, Killua and Leorio. The series' first antagonist is also introduced as one of the applicants. Hisoka, is a complex villain who uses playing cards as weapons, and who views Gon as an "unripe fruit" that he will take great pleasure in killing once he's grown up enough to present a challenge. Before the end of the Hunter Exam, Killua faces his brother, Illumi, who makes him come home before he can even finish the Exam.

After passing the Hunter Exam, Gon, Kurapika, and Leorio goes off a new adventure of springing Killua out from his parents' mansion in Kukuroo Mountain. After three reunite with Killua, Leorio leaves for medical school, so he can become a professional doctor, and Kurapika, to find work as a bounty hunter. Gon and Killua decide to go together in Heavens Arena to gain combat experience by training.

Gon and Killua goes to Heavens Arena, a 251-floor building where people compete through fighting tournaments around the clock for cash. It is here they meet the Kungfu master Wing, who teaches them about Nen, a chi-like energy that can be use to manifest superhuman powers. He teaches a young child named Zushi, who joins Gon and Killua to fight in the tournament to gain money and experience. Hisoka is also in the tournament. Gon finally get to battle Hisoka again, to show off how much he has improved.

The four main characters reunite for the world's largest auction in a sprawling metropolis called Yorknew City. Gon, Killua, and Leorio try different methods to make enough money to buy Greed Island, a Joystation video game that could help Gon find his father. Meanwhile, Kurapika works as a bodyguard for Neon Nostrade, flesh collector and daughter of the head of a Mafia family, in order for him to get closer to his clan's scarlet eyes that are said to to be auctioned at the said city. The Phantom Troupe, a group of thieves, who had slaughtered Kurapika's clan are also gathering at Yorknew City.

Gon, Killua, and Leorio return to help Kurapika’s recovery after defeating the Phantom Troupe. Leorio and Kurapika leave again, returning the focus to Gon and Killua. Gon and Killua are able to join a team hired by the billionaire, Battera, to play the game. Gon and Killua are joined and later Nen-trained by Biscuit Krueger, a 57-year-old woman who looks like a 12-year-old girl, and is a master and experienced teacher of Nen. As the story progresses, a player nicknamed the Bomber is blowing other players up. Gon, Killua, and Biscuit team up with other players and take the Bomber out. The Phantom Troupe also travels to Greed Island, looking for a Nen-Remover to remove the Nen dagger on Kuroro put by Kurapika to null his powers.

After leaving Greed Island, Gon and Killua meet up with Kite. They are all hire to investigate a strange insect leg that washed up on a beach. Genetic testing determines that the leg belongs to an abnormally large queen Chimera Ant which just happens to wash up on the shore of an island called the NGL (Neo Green Life). The Chimera Ants proceed to wipe most of the population out and spawn hundreds of offspring for next generation before Gon, Killua, and Kite arrive to stop her.

Netero, the hunter chairman has passed away after his confrontation with the Chimera Ant King, Meryem. A new hunter chairman is needed, so the zodiac twelve are gathered to establish a new election for their new hunter chairman. Ging Freecss, one of the zodiac twelve members is leading the establishment. Leorio returns and quickly rises to prominence as a top candidate in the election. These events act as a backdrop to the efforts of Killua and his servants, who wish to revive a hospitalized Gon using the Nen ability of Alluka Zoldyck. Illumi, aided by Hisoka, attempts to stop Killua due to the potential dangers attached to using Alluka's powers.