The story’s protagonist, Jake Sully (Sam Worthington), is a former U.S. Marine who was wounded and paralyzed from the waist down in combat on Earth. Jake is selected to participate in the Avatar program, which will enable him to walk. Jake travels to Pandora, a lush jungle-covered extraterrestrial moon filled with incredible life forms, some beautiful, many terrifying. Pandora is also home to the Na’vi, a sentient humanoid race, who are considered primitive, yet are more physically capable than humans. Standing three meters tall (approximately 10 feet), with tails and sparkling blue skin, the Na’vi live in harmony with their unspoiled world. As humans encroach deeper into Pandora's forests in search of valuable minerals, the Na’vi unleash their formidable warrior abilities to defend their threatened existence.

Jake has unwittingly been recruited to become part of this encroachment. Since humans are unable to breathe the air on Pandora, they have created genetically-bred human-Na’vi hybrids known as Avatars. On Pandora, through his Avatar body, Jake will be able to walk again. Sent deep into Pandora's jungles as a scout for the soldiers that will follow, Jake encounters many of Pandora's beauties and dangers. There he meets a young Na’vi female, Neytiri (Zoe Saldaña).

Over time, Jake integrates himself into the Na'vi clan, and begins to fall in love with Neytiri. As a result, Jake finds himself caught between the military-industrial forces of Earth and the Na’vi, forcing him to choose sides in an epic battle that will decide the fate of Pandora forever.