In the 1920s, Mr. MacDowell, a gifted astrologer, detected a supernatural being when entering his new house in Scotland. He gathered eminent mediums of his time for an extraordinary séance, and they have seven hours to make contact with the ghost and investigate any clues that it can give to unlock an old mystery. Unable to speak, the amnesiac ghost communicates with the mediums through visions, which are shown in the game by illustrated cards. The mediums must decipher the images to help the ghost recall how he was murdered: Who did the crime? Where was it? Which weapon was used? The more the mediums cooperate and guess correctly, the easier it is to catch the right culprit.

In Mysterium, a reworking of the game system present in Tajemnicze Domostwo, one player is the ghost while everyone else represents a medium. To solve the crime, the ghost must first remember (with the aid of the mediums) all of the suspects present on the night of the murder. A number of suspect, location and murder weapon cards are put on the table, and the ghost randomly gives one of each of these in secret to a medium. Each hour (i.e., game turn), the ghost gives one or more vision cards face up to each medium, refilling their hand to seven each time they share vision cards. These vision cards give dreamlike images to the mediums, with each medium first needing to deduce which suspect corresponds to the vision cards received.

Once the ghost has handed cards to the final medium, they begin a two-minute sand timer. Once a medium has placed their token on a suspect, they can also place clairvoyancy tokens on the guesses of other mediums to show if they agree or disagree with those guesses. When time runs out, the ghost reveals to each medium whether the guesses were right or not. Mediums who guessed right move on to guess the location of the crime (and then the murder weapon), while those who did not, keep their vision cards and receive new ones next hour corresponding to the same suspect. Once a medium has correctly guessed the suspect, location and weapon, they move their token to the epilogue board and earn one clairvoyancy point for each hour left on the clock. They can still use their remaining clairvoyancy tokens to score more points. if one or more mediums fail to identify the suspect, location and weapon before the end of the seventh hour, then the ghost has failed and disappears, leaving the mystery unsolved.

However, if they have all succeeded, then the ghost has recovered enough of its memory to identify the culprit. Mediums then group their suspect, location and weapon cards on the table and put a number by each group. The ghost then picks one group, places the matching culprit number face down on the epilogue board, selects three vision cards — one for the suspect, one for the location, and one for the weapon — then shuffles these cards. Players who have received few clairvoyancy points flip over one vision card at random, then secretly vote on which suspect they believe is guilty; players with more points then flip over a second vision card and vote; then those with the most points see the final card and vote.

If a majority of the mediums have identified the right suspect, with ties being broken by the vote of the most clairvoyant medium, then the killer has been identified and the ghost can rest in peace. If not, perhaps you can attempt it again...