The achievements "School's Out For Summer" (awarded for clearing School Mode for the first time) and "School's Out Forever" (awarded for unlocking all endings in School Mode) are named in reference to the chorus of the song "School's Out" by Alice Cooper.

For the game's English dub, Spike Chunsoft requested that NIS America keep Monokuma's name intact. He would end up becoming the team's favorite character to localize, working to keep him both funny and threatening like in the Japanese version. This, however, led to difficulties finding a suitable voice actor for the character, as they wanted somebody that could embody Monokuma's "hyperactive psychopathic nature", not helped by how beloved the original Japanese voice actress was. When asked what Monokuma was like in the English version, script editor Phoenix Spaulding stated:

During a Q&A with Kotaku in 2015, it was noted that both Danganronpa: Trigger Happy Havoc and Danganronpa 2: Goodbye Despair had a female character that appeared to have been designed to be the player/main character's favorite, the former game having Kyoko Kirigiri and the latter game having Chiaki Nanami. When asked if this was intentional, series creator Kazutaka Kodaka stated:

In an attempt to surprise players, Kazutaka Kodaka decided to have Sayaka Maizono, who was promoted as the game's heroine, Spoiler:be killed off in the first chapter. Afterwards, it would then be revealed that she had planned to Spoiler:frame Makoto Naegi for a murder she had attempted to commit. This was intended to have a major impact on not just the player, but also the character Makoto, as it would result in him developing bad feelings about how he would be treated.

The game was originally created with the name "Distrust", and was originally designed to be far darker and sinister than that of the final release.

Although the executions for Spoiler:Sayaka, Kiyotaka, Yasuhiro, Byakuya, Chihiro, Touko, Aoi, Sakura, and Spoiler:Hifumi were never seen in the game, each character did have their own personal executions designed for them, which can be found in the Official Danganronpa Art Book.

Spoiler:Hifumi's execution has one more detail of note; while it was never put into the game, it did appear in the manga adaptation of "Danganronpa 1 (Trial Version)", a demo released exclusively in Japan. Referred to as "Kiwotsukete, Buko-hime! Dai Kaijū Shinkō!!" (translated to "Watch Out, Princess Buuko! Great Monster Invasion!!), it involves a giant Princess Buuko and Monokuma fighting each other, with Spoiler:Hifumi caught in the middle, ending with him dying after being hit by 'Certain Kill' beams from both simultaneously. This makes it the only execution to never be put into the game, but still be put into an official source outside the artbook.

In the Vita version of the game, the trophies "Despair's Last Reward", and "Nine Coins, Nine Purses, Nine Bears" are references to the Zero Escape series, which was also developed by Spike Chunsoft. More specifically, the games Virtue's Last Reward and Nine Hours, Nine Persons, Nine Doors.