The main plot of Man of Medan is presented as an unfinished story in the possession of the omnipresent Curator (Pip Torrens), who requests the player's assistance in completing it. Decisions made by the player alter the outcome of the story and the fates of its characters. Prologue (1947) In post-World War II, an American warship is stopping in a Chinese port while making the final preparations to set sail. Joe and Charlie, two privates of the ship, are on Manchuria's shore leave and wander in a market. While they take turns playing punch dummy games in one of the multiple stores, they also consult a fortune teller who predicts them death and doom.

Back on the ship, both are caught and arrested by one of the sergeants due to their drunkenness and roughhousing. A couple of nights after, Joe wakes up in the sick bay but manages to get out after encountering a corpse in a first aid locker. Joe finds and frees Charlie in a seemingly empty ship. However, they encounter the same sergeant who arrested them. As they hide, they see him acting strange and paranoid with a submachine gun. Going down the cargo hold 3, Joe and Charlie discover dead bodies.

Getting separated, they both encounter threatening beings in cargo hold 2 that will end up killing both of them. Present Day (2019) As soon as the prologue ends, the player is introduced to the Curator, who introduces himself explaining his entire role while being the accomplice of the player and recording everything that happens as the story progresses. In the present day, brothers Brad and Alex, along with Alex's girlfriend Julia and her brother Conrad, begin boarding on Fliss' boat, the Duke of Milan, hoping to find a WWII wreck plane that is rumoured to have crashed in the South Pacific Ocean.

As their guess was right, Alex and Julia dive into the wreck to investigate it and possibly find some sort of treasure, as they are souvenir sellers. Back up on the surface, Conrad and Fliss encounter a group of three fishermen who get their speedboat damaged by the Duke of Milan's recoil cable, which was connected to the underwater wreckage. The fishermen ask reparation but Conrad dismisses them mockingly.

As soon as the couple emerges from their "underwater mission", the five protagonists spend the sunset on the Duke's outside deck while discussing the coordinates Alex and Julia found while exploring the wreck. The player is then taken back to the Curator's repository, as he shortly discusses the personality of each character. He also adds the player has made choices that the protagonists will value later on. During the night, the three fishermen, Olson, Junior and Danny ambush the Duke's crew and take the protagonists hostage, except Brad, who managed to hide.

The rest of the group is tied up in the biggest cabin. As Fliss is taken outside with the fishermen, Conrad gets the idea of attacking them directly or breaking a window in order to flee with their speedboat. Conrad can flee successfully or die trying. Danny then discovers the coordinates of the Manchurian Gold and shows it to Olson, the leader of the fishermen, who decide to retrieve the treasure and brings the prisoners along.

The Curator comments on the outcome of the attack and offers a bit of advice to the player saying that everything is not as they should be, regretting he should not have said that thereafter. After getting thrown around in an intense storm, the Duke crashes into a rusty freighter from WWII: the abandoned SS Ourang Medan. The fishermen decide to board the ship, and Junior takes the distributor cap from the Duke so that the protagonists can't escape via that boat.

Minutes after boarding the ship, the fishermen lock the protagonists in a dark room, where they manage to escape. As soon as the protagonists and the three antagonists are split, the first group explore the ship in order to find a way out and to retrieve the distributor cap needed for starting the Duke of Milan. On their way, Fliss (and maybe Brad if not hidden) gets captured while attempting to retrieve the boat's engine.

Meanwhile, in the main deck, Alex, Julia and Conrad try to separate and later go for their captured companion(s). Later on, in the workshop situated in the freighter's lower deck, Fliss is forcefully escorted by one of the pirates, Danny, who later flees and disappears in a panic after seeing some unknown threat. Fliss (along with Brad's company or not) continues her way exploring the ship's cold corridors until ending up in an out of place ballroom, where she will bump with a hooded figure, unless she exits the room for a moment and discovers the room appearing rusted and flooded like the rest of the ship.

If Brad managed to hide earlier, he will enter the ship by this point, trying to follow the trail of his friends. He will eventually fall off a ledge and find Fliss.