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Danganronpa V3: Killing Harmony has a structure similar to the first and second games in the series: the story is split into six chapters, and each chapter is split into three parts (with the exception of the last, which only has two). Daily Life can be considered the chapter's opening, usually setting up the mystery to come. In Daily Life, the player can explore their surroundings and bond with fellow students via Free Time opportunities. In Deadly Life, the player must investigate a murder, collecting evidence in the form of Truth Bullets. In the Class Trial, the player must use the evidence they have collected to overcome a variety of challenges that will eventually lead them to the truth.

At the start of the game, you are given the option of three difficulties for the game's logic and action segments: Gentle, Kind, and Mean. A higher difficulty will affect the logic segments by giving you more Truth Bullets to choose from in Nonstop Debates, as well as having a greater impact on your influence if you answer a question wrong. The more action-driven mini-games comprise the action segments of the game, such as Rebuttal Showdown and Argument Armament, though a higher action difficulty will also produce more white noise to shoot down in Nonstop Debates. These will ultimately be more difficult even with the help of a walkthrough, but you will be rewarded with a greater amount of Monocoins the higher the difficulty. Choose whichever difficulty seems best based on prior (or lack of) experience with the series (though it is highly recommended that Trigger Happy Havoc and Goodbye Despair be played first for story purposes), and start your Dangan experience with the Prologue.