Bill Tiller has stated that the inspiration for Murray came from a talking skull that he bought at Disney World while on vacation. He brought it into the office, subsequently scaring, amusing, and annoying his co-workers.

In "Part VI: Guybrush Kicks Butt Once Again", there was originally a scene where Guybrush is seen waving to Elaine who had escaped from LeChuck and, in a fight, changes the track of the roller coaster so Guybrush isn't sent to the pool of lava. Although cut from the game, the storyboards of the scene were however made available in the official strategy guide.

An animated image of Guybrush waving which matched the scene was seen in an advertisement for the game in German magazine "Bravo Screenfun".

The Curse of Monkey Island was the last LucasArts game to use the SCUMM engine, the engine used for LucasArts adventure games from the late 1980s and 1990s.

An entire song, a duet between Guybrush & Elaine called 'Plank of Love', was cut from the end credits.

The lyrics had been written, but the production team ran out of time to record it.

The game was dedicated in memory of Brett Barrett, a tester for The Secret of Monkey Island and a programmer on Monkey Island 2: LeChuck's Revenge, who had died in a motorcycle accident the year before.

In Part III: Three Sheets to the Wind, the performance of the song "A pirate I was meant to be" was not played in non-English versions of the game. It's speculated the section was removed due to its intense usage of English rhymes, which would have been difficult to translate.

If the player examines the crumbling hole in the Goodsoup Family Crypt, Guybrush will attempt to squeeze through it, and will poke his head up into the Mêlée Island forest from The Secret of Monkey Island. He'll comment that it seems familiar, before returning to the crypt to escape "a terrifying horde of stunningly-rendered rabid jaguars".

At the Blood Island beach, choosing to "Pick Up" the seawater about 26 times will cause Guybrush to walk into the water, where he'll appear under the Mêlée Island pier from The Secret of Monkey Island. There he will find his own drowned corpse from that game, on which he'll comment "Hmmm... That guy probably couldn't hold his breath underwater for very long." and walk off.

There is a large spider web inside "The Mutual of Stan". If the player inspects it, then leaves and returns 35 times, a struggling Maggie from The Dig will appear on the web, and then be eaten by a giant spider.