Sissel, the spirit of a recent murder victim, wakes up to realize that he is dead, and has also lost his memories. The only lead he can see is a young detective named Lynne, who is then killed by an assassin. However, upon talking to another spirit named Ray, Sissel learns he possesses the ability to perform Ghost Tricks, in which he can possess inanimate objects, and can travel to four minutes before a person's death and alter their fate. Using these tricks, Sissel manages to rescue Lynne, who is investigating something big happening this night while being under suspicion of murder. With Ray's warning that his soul will disappear come dawn, Sissel decides to team up with Lynne in order to help each other. As Sissel continues his investigation, he saves Lynne several times, along with a dog named Missile. Eventually, Sissel stumbles upon security cam footage that allegedly shows him being killed by Lynne, but he continues to help her out despite this knowledge. Meanwhile, Lynne asks Sissel to help out a former detective named Jowd, who was put on death row after an incident concerning his daughter Kamila led to the death of his wife.
After managing to delay Jowd's execution, Sissel soon learns that Kamila had been kidnapped by the organization that targeted Lynne and arranged for Jowd's execution. They also learn of the existence of a "manipulator", who allegedly caused the death of Kamila's mother. While continuing to find ways to save people and rescue Kamila, Sissel once again encounters Missile, who had died once again but has gained the Ghost Trick of swapping similarly shaped objects and decides to help Sissel rescue Kamila. Soon, they find that the body that Sissel thought was his own is walking around and has his own set of Ghost Tricks. It is revealed this man was involved in an incident ten years ago in which he took Lynne hostage while escaping from Jowd, but was killed by a strange meteorite shard with strange properties, the radiation of which gives spirits their Ghost Tricks, his being to manipulate living beings. Sissel, Missile, Jowd and Lynne go to a submarine where the mysterious man tries to possess Kamila and attack Lynne, but is betrayed by the organization leader, Sith, who steals the meteorite within his body and tries to sink the submarine with everyone in it. After getting Lynne and Kamila to safety, Sissel once again encounters the manipulator now known as Yomiel. He explains his motives for revenge, which included controlling Lynne to shoot himself and making a deal with the organization to get Jowd executed. Refusing to give up in a seemingly hopeless situation, Sissel and Missile ride a torpedo over to an escape pod where they find Jowd dead and Yomiel's lifeless body and travel back 10 years to the four minutes before his death, where the three of them use their combined Ghost Tricks to stop Yomiel from being killed by the meteorite, thus rewriting everyone's fate from that point onwards.
Following this, it is revealed that Sissel's true identity is that of Yomiel's pet cat, who was accidentally killed when he manipulated Lynne to shoot at him. Ray also appears and reveals himself to be an older version of Missile from an alternate future in which he was unable to change anyone's fate, but managed to travel back in time and teach Sissel about his Ghost Tricks in order to set things right. He also reveals that he lied about "disappearing by dawn" so that Sissel would solve the mystery in one night, before Yomiel was to be trapped at the bottom of the sea, at which point it would have been impossible to reach Yomiel and stop his death. Sissel returns to a new present, in which he is a happy cat living with Jowd's family, but still is a kitten and having Ghost Tricks due to having a meteor fragment embedded in him 10 years ago, and is soon reunited with Lynne, while Yomiel finishes his prison sentence, going back to his fiancée.
Most of the game is played out on the bottom screen. Sissel's spirit is controlled by touching and dragging it with the stylus. Sissel's "Powers of the Dead" prevent him from controlling people directly, but he can affect the situation by possessing and manipulating the inanimate objects around him. There are hundreds of items in the game, each specific to their own areas, many of which contain unique "Ghost Tricks" that Sissel can perform. The difficulty in many of the puzzles arises from the fact that Sissel's spirit has a limited radius that it can move in when jumping from object to object.
The other major aspect of Ghost Trick is time travel. Sissel will often come across dead bodies which may be helpful to his search for the truth and change the fate of the victim. After talking and getting info from the person's spirit, the game rewinds back to exactly four minutes before their death. The player then has a certain amount of time to use Sissel's item manipulation skills to help prevent the character's demise.
Outside of the trick-based puzzles, Sissel is able to navigate through the city at his leisure by traveling through telephone lines. He can discover new locations by using his powers to trace a phone call. During sections in which Sissel travels into the past, he is only able to travel between phones that are currently connected, and if either party hangs up he will be unable to travel to the other location.