As opposed to most games based on mythology, Titan Quest is based on the end of the communication between the Gods and Humanity. The main character (whose name and sex is chosen by the user) begins the quest on a dirt road near a small village named Helos. The town and all of Greece have been overrun by beasts and creatures that are terrorizing the countryside wrecking harvests, burning farms and olive groves, invading villages and cemeteries, etc. After being sent on a mission to Delphi by the Spartan general Leonidas, the hero finds Centaurs, Satyrs, Minotaurs, Gorgons, Demons and Skeletons relentlessly guard the way to prevent the hero from reaching the next village or town. Battling from one rebirth fountain to the next through miles of infested countryside and caves, the hero earns a brief reprieve in the fictional historic recreations of Delphi, Athens, and Knossos. In each town or village the hero passes through the storyline is expounded through interaction with non-player characters. The cause of the havoc is eventually gleaned from the representatives of an organization called "The Order of Prometheus." A mythical lesser Titan called a Telkine has apparently destroyed the communication "conduit" used by the ancient priests and oracles to contact the Gods. After defeating the first Telkine in a fierce battle under the palace of Knossos, the hero then travels to Egypt in an attempt to reconnect communication through rituals hidden in a sacred scroll. But the rituals fail and the character has to fight another Telkine in the Valley of the Kings along with Egyptian mythical creatures in and around Giza and the Nile. The search for the final Telkine takes the hero along the Silk Road to the Orient, battling yetis, Myrmidons and the Terracotta Army along the way with stops in the Hanging Gardens of Babylon, the Himalayas, Mongolia, and the Great Wall of China. Chasing down the final Telkine proves difficult as the ememies grow eminently more powerful. Reaching the Jade Palace in China, the Yellow Emperor warns the hero that the Telkine has made its way to release the Titan Typhon from his earthly grave. At the Wusou Mountains the hero discovers that Typhon has made his way to Olympus. After killing the final Telkine, the hero must travel through a portal to reach Olympus and battle Typhon. Upon reaching Olympus and defeating Typhon, Zeus the king of the Greek Gods, thanks the hero for their courage and talks about the break in connection with the gods.
The game then has an "Epic" level and then a "Legendary" level in which the monsters and battles in the storyline become significantly more difficult.