The DanganRonpa series takes its twisted, kill-or-be-killed game of whodunit to the tropical paradise of Jabberwock Island in Goodbye Despair. Players assume the role of Hajime Hinata, a student at the prestigious Hope's Peak Academy, but what was supposed to be a peaceful class trip turns into chaos when Monokuma, a demented robot bear who happens to be the school's headmaster, refuses to let anyone leave the island unless they murder a classmate without being caught. Once a body is discovered, gamers must conduct an investigation, hold a trial, and deliver a verdict.

During the investigation phase, players earn Truth Bullets by heading to the crime scene to look for clues, examine objects, and interview classmates. Gamers then head into the class trial phase, during which they will engage in heated debates with classmates and use Truth Bullets to shoot down weak points in their arguments. These debates can also lead to mini-games, such as the spelling-based Hangman's Gambit, or the virtual skateboarding of Logic Dive. If players make convincing arguments their Influence Gauge will rise, but if the gauge reaches zero, the truth will never be known.

Goodbye Despair also includes a number of more light-hearted options. When not conducting an investigation, gamers can spend their free time getting to know their classmates, forming bonds with them, and even buying them gifts. The Dangan Island mode removes Monokuma from the equation and lets the classmates work together to accomplish various goals around the island. The game also includes a story from the writer of Trigger Happy Havoc, and the action mini-game Monomi's Miracle Magic.