Former Marine Jake Sully arrives on Pandora in place of his murdered twin brother. Introduced to Dr. Grace Augustine's Avatar Program, Jake is linked to a lab-grown Na'vi body. While learning to walk again in avatar form, Colonel Miles Quaritch promises Jake financial backing for reconstructive leg surgery on Earth if Jake infiltrates the local Omaticaya clan to secure intelligence for their relocation.
During an expedition, Jake is separated from his team and attacked by Pandoran predators. Neytiri rescues him after seed-spirits of Eywa land on him, marking him as spiritually significant. Neytiri takes Jake to Hometree, where her mother, Tsahìk Mo'at, orders Neytiri to teach Jake their ways.
Over months, Jake learns to hunt, tame an Iknimaya banshee, speak Na'vi, and make Tsaheylu. He falls in love with Neytiri and is accepted into the tribe. After Jake and Neytiri mate before the Tree of Voices, RDA bulldozers advance to destroy the site. Jake attempts to destroy a bulldozer camera, exposing his dual identity.
When Jake reveals to the Omaticaya that he knew the humans intended to attack Hometree, Neytiri and the clan reject him as a traitor. Quaritch launches a devastating assault on Hometree, destroying it with incendiary missiles, killing Neytiri's father, Chief Eytukan, and scattering the tribe.
Imprisoned by RDA forces, Jake, Grace, and Norm are freed by rogue pilot Trudy Chacón. During their escape, Grace is shot by Quaritch. To regain the trust of the Na'vi, Jake tracks and tames Toruk, becoming the legendary warrior Toruk Makto. Reunited with Neytiri and the Omaticaya, Jake brings Grace to the Tree of Souls, asking Eywa to permanently transfer Grace's consciousness into her Avatar. Grace is too weak and dies, but her soul merges with Eywa.
Jake rallies all Na'vi clans for war. In the final battle, human air support initially devastates the Na'vi war party. When all seems lost, Pandora’s wildlife joins the battle en masse—Eywa answers Jake’s prayer. Neytiri kills Quaritch with two arrows just as Jake's human body suffocates in a breached link unit.
With the RDA defeated, the humans are expelled from Pandora, except for a select few scientists. In the final sequence, the Omaticaya perform the sacred ritual at the Tree of Souls, permanently transferring Jake's consciousness from his dying human body into his Na'vi Avatar. The film closes on a sharp close-up as Jake opens his Na'vi eyes—fully reborn.