The events of Hotline Miami 2: Wrong Number are presented out of chronological order: before, during, and after the events of the original, focusing on events in 1985, 1989, and 1991 respectively.

Hotline Miami 2 serves as both a sequel and a prequel to the original game. While the first game only put you in the role of one character, Hotline Miami 2 follows nine different characters in their personal stories.

Jacket is the very last character shown to die in the entire series, being killed by a nuclear blast in his prison cell during the credits of Hotline Miami 2: Wrong Number.

Hawaii is nuked, killing Richter and his mother. Miami is nuked, killing Detective Manny Padro, who is locked up in his apartment thinking that the cops are on the him being the Miami Mutilator. Evan, who depending on what you do earlier in the game, is either seen with his family, or writing a book alone.