Despite their differences in position, three men—the youngest senior executive of the Port Mafia, Osamu Dazai; the lowest ranking member, Sakunosuke Oda; and the intelligence agent, Ango Sakaguchi—gather at the Lupin Bar at the end of the day to relax and take delight in the company of friends. However, one night, Ango disappears. A photograph taken at the bar is all that is left of the three together. Fast forward to the present, and Dazai is now a member of the Armed Detective Agency. The Guild, an American gifted organization, has entered the fray and is intent on taking the Agency's work permit. They must now divide their attention between the two groups, the Guild and the Port Mafia, who oppose their very existence.

A large-scale catastrophe is occurring across the planet. Ability users are discovered after the appearance of a mysterious fog, apparently having committed suicide, so the Armed Detective Agency sets out to investigate these mysterious deaths. The case seems to involve an unknown ability user referred to as Collector, a man who could be the mastermind behind the incident. Trust and courage are put to the test in order to save the city of Yokohama and ability users across the world from the grip of Collector where the Armed Detective Agency forms an unlikely partnership with the dangerous Port Mafia.

For weeks, Atsushi Nakajima's orphanage has been plagued by a mystical tiger that only he seems to be unaware of. Suspected to be behind the strange incidents, the 18-year-old is abruptly kicked out of the orphanage and left hungry, homeless, and wandering through the city. While starving on a riverbank, Atsushi saves a rather eccentric man named Osamu Dazai from drowning. Whimsical suicide enthusiast and supernatural detective, Dazai has been investigating the same tiger that has been terrorizing the boy. Together with Dazai's partner Doppo Kunikida, they solve the mystery, but its resolution leaves Atsushi in a tight spot. As various odd events take place, Atsushi is coerced into joining their firm of supernatural investigators, taking on unusual cases the police cannot handle, alongside his numerous enigmatic co-workers.

No longer concerned with military affairs, Yukichi Fukuzawa intends to act as a lone bodyguard-for-hire, making use of his deadly swordsmanship. However, things are not going as planned for his freelance business, and that is when he crosses paths with a mouthy boy named Ranpo Edogawa. While their initial interactions are intertwined with a bizarre murder mystery, the aftermath prompts the formation of the Armed Detective Agency. Presently, Ranpo finds himself chasing down a gifted individual with the dangerous ability to execute the perfect crime. But as the great detective unravels the case, he soon discovers an elaborate plot to obliterate the Agency in its entirety. Although forewarned of the trap, the Agency continue their pursuit of the criminals, only to end up framed for the crime themselves. Now branded as wanted terrorists, the remaining members must find a way to prove their innocence—even if they must turn to sworn enemies for assistance.