The Last Guardian is a 3D platform game with puzzle elements set in a fantasy world. The story centers around the bond between a little boy and a huge Griffin-like creature called Trico. It is framed as a flashback as the boy, now an old man, narrates the events. At the start of the game the boy wakes up in a cave. He has been kidnapped and was taken to a large castle. He discovers tattoos that he previously did not have on his body and he also immediately meets Trico, wounded and chained up, next to him. The boy frees him, removes the spears from his body and feeds him to bring back his energy. While Trico is hostile at first, he warms up to the boy and then throughout the game the two work together to escape the castle and to fight the guards that attempt to recapture them. The player only controls the boy and has to learn to work with Trico and issue commands to coerce it into specific actions. That does not always work right away, as in some cases Trico can become distracted or stubbornly acts by his own instincts and interests. The player can also often choose to keep it close through commands or to let it roam freely.

Interaction with Trico is needed for almost all of the puzzles. The boy can ride his back and reach high places that way. The creature can also jump over large gaps. The boy can move around by himself, climb platforms, carry objects and interact with levers and other objects. Trico does all the fighting against the guards with his mighty claws and the boy has to stay out of the way. The creature is however vulnerable to spears and the boy can climb him to pull them out. In the later parts of the game more cooperation during fights is needed as Trico becomes scared of a symbol and the boy has to work around that. He can also shoot lighting out of his tale and in later parts of the game the boy uses a shield to redirect the stream for attacks or to solve puzzles.

Sometimes the boy can be captured and dragged away by a guards and then he has to wriggle free. The boy speaks an unknown language and communication between the two is largely nonverbal. The boy has to interpret Trico's body language to figure out when he is afraid, angry or hungry and then interact with the environment to change his mood or find food. Trico also often provides subtle hints of where to go next through his gaze. The beast can be pointed in a certain direction by throwing barrels to draw his attention. Throughout the game the boy learns more ways of control over Trico by issuing commands for directions, jumping or moving down.