In ages long forgotten, when Earth found itself on a collision course with a meteor, Legendary Pokémon Arceus used its power to avert the danger. However, this feat caused the 16 Plates surrounding it to scatter across the world. Without the Plates providing Arceus with life energy, it began to die. A human named Damon managed to find one of the Plates and returned it to the moribund Pokémon, helping it recover. As a reward, Arceus created the Jewel of Life and gave it to the people of Michina Town, stipulating that it must be returned, but the humans refused, hogging the Jewel to themselves. In the battle that ensued, Damon was killed and Arceus went into slumber, vowing to punish humanity upon its return. Satoshi and his companions arrive in Michina Town where they come across Sheena, a descendant of Damon, who claims to be in possession of the Jewel of Life and intends on giving it back to Arceus when it awakens. The situation takes an unexpected turn when Arceus, despite Sheena's best intentions, remains unsatisfied. Satoshi must now prevent the destruction of the entire human race, as Arceus' fury causes distortions in the fabric of the universe, enraging the Legendary trio—Dialga, Palkia, and Giratina—and disturbing the world's balance.

Using the fossil of the Legendary Pokémon Mew, Team Rocket has created the first successful Pokémon clone. Named Mewtwo, the man-made Pokémon quickly becomes upset with the circumstances of its creation and goes on a rampage. It is soon approached by Sakaki, the leader of Team Rocket, and is manipulated into committing evil acts. Repulsed by the tricks of mankind and the cruelties it has suffered, Mewtwo isolates itself from everyone and plots against humans whilst trying to discover its true purpose in life. Disguising as the world's strongest Pokémon trainer, Mewtwo draws in the region's most powerful trainers who want to fight the new, mysterious opponent. With the fate of the world at stake, renowned trainers Satoshi, Takeshi, and Kasumi must battle against Mewtwo and defeat it before it brings about the downfall of humanity.

The beautiful Alamos Town is home to a pair of century-old structures known as the Space-Time Towers, built by the architect Godey to play orchestral music in the area. The towers are also home to the Alamos Town Contest Hall, which is the next destination for Hikari, Satoshi, and Takeshi in their journey through the Sinnoh region. A woman named Alice and her partner Chimchar are happy to guide Satoshi and his friends through the town and its hallmarks. But the tour is suddenly interrupted when Alice's friend Tonio notices a wave of dimensional disturbances throughout the town—all of which is blamed on an ominous Pokémon named Darkrai. The space-time disturbances continue to intensify as two legendary Pokémon, the Temporal Pokémon Dialga and the Spatial Pokémon Palkia, appear to duel each other, isolating the town and everyone present in it from the world into another dimension! As he learns that this event was foreseen long ago, Tonio finds that his great-grandfather left behind a way to stop the dueling Pokémon. Will Satoshi and his friends be able to use this last resort to save Alamos Town from vaporizing between the dimensions?

The legendary Renegade Pokémon, Giratina, encounters the Temporal Pokémon Dialga by a lake and successfully manages to drag Dialga into its home—an alternate dimension separate from the normal world. But a small green Pokémon gets gotten dragged in as well—and though it somehow escapes, Dialga uses this opportunity to escape as well after preventing Giratina from chasing after it. After accidentally ruining Satoshi and his friends' picnic, the green Pokémon is taken to the Pokémon Center where it is treated for injuries and introduced as Shaymin, the mythical Gratitude Pokémon. Using telepathy, Shaymin demands that Satoshi, Hikari, and Takeshi take it somewhere. But before they can find out where to go, the group find themselves being pursued by both Giratina and a strange man named Zero—both in search of little Shaymin! Will Satoshi and his friends be able to find Shaymin's desired place while keeping themselves out of danger?