"Durarara!!×2 Ketsu Gaiden!?" serves as a side story to the main "Durarara!!×2 Ketsu" arc, focusing on the chaotic and interconnected lives of characters in Ikebukuro. The narrative delves into the aftermath of the events in "Durarara!!×2 Ketsu," exploring unresolved tensions and new developments within the city. Central to the story is the ongoing power struggle between the Dollars, the Yellow Scarves, and the Blue Squares, with their leaders—Mikado Ryuugamine, Masaomi Kida, and Aoba Kuronuma—navigating shifting alliances and personal conflicts.

The series also highlights the enigmatic Izaya Orihara, whose manipulative schemes continue to influence the city's dynamics. His interactions with Shizuo Heiwajima, a man with superhuman strength, remain a focal point, as their longstanding feud escalates. Meanwhile, Celty Sturluson, a Dullahan searching for her missing head, faces new challenges as her relationship with Shinra Kishitani deepens, and her presence in Ikebukuro draws further attention from both humans and supernatural entities.

Other key characters, such as Anri Sonohara, who harbors the cursed sword Saika, and Simon Brezhnev, a Russian sushi chef with a mysterious past, play significant roles in the unfolding events. The narrative weaves together multiple perspectives, revealing how individual actions ripple across the city, creating a complex web of intrigue, betrayal, and unexpected alliances. Themes of identity, loyalty, and the consequences of one's choices are explored as the characters confront their pasts and grapple with their roles in Ikebukuro's ever-changing landscape. The series maintains the signature blend of urban chaos, supernatural elements, and character-driven storytelling that defines the "Durarara!!" franchise.