In 1969, young boys Kenji, Otcho, Yoshitsune and Maruo build, in an empty field, a hideout they call their secret base, in which they and their friends can get together to share manga and stolen pornographic magazines and listen to a radio. To celebrate the event, Otcho draws a symbol for the base that would represent their friendship. After their friends Yukiji and Donkey join the gang, they imagine a future scenario where villains would try to destroy the world, and in which the boys would stand up and fight; this scenario is transcribed and labelled Book of Prophecy (よげんの書 Yogen no sho?).
The series itself opens in the late 1990s, where Kenji is a convenience store owner, finding solace in his childhood adventures as he takes care of his baby niece Kanna and his mother. After Donkey is reported to have committed suicide, Kenji stumbles upon a large cult led by a man known only as "Friend". The cult has a plan to destroy the world on New Year's Eve of 2000, (referred to in the latter half of the story as the Bloody New Year's Eve), and the events that are currently unfolding are suspiciously close to the plan documented in the Book of Prophecy. Kenji begins to recruit some of his older friends, including Otcho and Yoshitsune, in an attempt to stop Friend.
The series spans several decades, from 1969 to 2017, which in the chronology of the series, becomes 3FE (3rd Year of the Friend Era). The series makes two distinct timeline cuts during the story; one from 2000 to 2014, and one from 2014 to 3FE. Several parts of the series are also told in flashbacks to previous events as the characters attempt to unravel the mystery of who Friend is and how to stop his plans of world destruction; most of the children's backstories through the 70s and 80s are told in this fashion.
Overall, the plot follows the friends as they initially try to piece together what the Book of Prophecy contained, and eventually attempt to predict the next attack, which begins with biological attacks on San Francisco and London, followed by a series of bombings at a major Japanese airport. The attack on the eve of 2000 involves a "robot", which is revealed to be a giant balloon with robotic appendages. Kenji manages to get inside the robot to plant a bomb in it, and is presumed killed when the bomb explodes. From this event, in which Friend uses a monument to destroy the robot, Friend and the Friendship Democratic Party (友民党 Yūmintō?), his titular political group, gain widespread political and even religious power, as Friend is slowly beginning to be viewed as a religious icon. Friend then reveals a new plan, a continuation of the Book of Prophecy, in which he plans to kill every human being on Earth except for 3 million of his friends, but he is then assassinated by his chief scientist. Following this, Friend's funeral becomes a worldwide spectacle, held in a stadium with the Pope giving the address. Partway through the service, Friend appears to rise from the dead and is shot in the shoulder by his own assassin. Friend makes it appear like he saved the Pope, leading him to worldwide acclaim.
The final portion of the story takes place in a newly remodeled Japan, under the "Era of Friend", who has instituted numerous bizarre changes, including the establishment of an Earth Defense Force, reputedly to protect Earth from an imminent alien invasion. During this time frame, Kanna, who is revealed to be Friend's daughter, leads an insurgency against Friend's government, enlisting the aid of numerous groups, including the survivors of rival gangs and mafia organizations. During this, Kenji, apparently also risen from the dead and carrying his trademark guitar, reappears.