To explore Pandora's biosphere, scientists use Na'vi-human hybrids called 'avatars', operated by genetically matched humans; wherefore Jake Sully (Sam Worthington), a paraplegic former marine, replaces his twin brother Tom as an operator thereof. Dr. Grace Augustine (Sigourney Weaver), head of the Avatar Program, considers Sully an inadequate replacement and assigns him as a bodyguard. While protecting the avatars of Grace and scientist Norm Spellman (Joel David Moore) as they collect biological data, Jake's avatar is attacked by a thanator and flees into the forest, where he is rescued by Neytiri (Zoe Saldana), a female Na'vi. Upon sight of an auspicious portent, she takes him to her clan, whereupon Neytiri's mother Mo'at (C. C. H. Pounder), the clan's spiritual leader, orders her daughter to initiate Jake into their society.
Colonel Miles Quaritch (Stephen Lang), head of RDA's private security force, promises Jake that the company will restore his legs if he gathers intelligence about the Na'vi, on grounds that they occupy the richest deposit of unobtanium in the area. When Grace learns of this, she transfers herself, Jake, and Norm to an outpost. Over three months, Jake grows to sympathize with the natives. After Jake is initiated into the tribe, he and Neytiri choose each other as mates; and soon afterward, Jake reveals his change of allegiance when he attempts to disable a bulldozer that threatens to destroy a sacred Na'vi site. When Quaritch shows a videograph of Jake's attack on the bulldozer to Administrator Parker Selfridge (Giovanni Ribisi), and another in which Jake admits that the Na'vi will never abandon Hometree, Selfridge orders Hometree destroyed.
Despite Grace's argument that destroying Hometree could damage the Biological neural network native to Pandora, Selfridge orders Jake and Grace to convince the Na'vi to evacuate. When this fails, Quaritch's forces destroy Hometree, killing Neytiri's father and many others. Mo'at frees Jake and Grace; but they are detached from their avatars and imprisoned. Pilot Trudy Chacón (Michelle Rodriguez), disgusted by Quaritch's brutality, carries them to Grace's outpost; but during the escape, Quaritch injures Grace.
To regain the Na'vi's trust, Jake connects his mind to that of Toruk, a dragon-like predator feared and honoured in Na'vi history. Thus connected, Jake finds the refugees at the sacred Tree of Souls and pleads with Mo'at to heal Grace. The clan attempts to transfer Grace from her human body into her avatar with the aid of the Tree; but she succumbs to her injuries before the process can be completed.
Supported by the new chief Tsu'tey (Laz Alonso), who acts as Jake's translator, Jake speaks to unite the clan and tells them to gather other clans for battle against the RDA. On the eve of battle, Jake prays to Eywa, via a neural connection to the Tree of Souls, to intercede on behalf of the Na'vi. Having noticed this convention, Quaritch organizes a pre-emptive strike against the Tree of Souls, believing that its destruction will demoralize the natives.
During the subsequent battle, the Na'vi suffer heavy casualties, including Tsu'tey and Trudy; but are rescued when Pandoran wildlife unexpectedly join the attack and overwhelm the humans, which Neytiri interprets as Eywa's answer to Jake's prayer. Jake destroys a makeshift bomber before it can reach the Tree of Souls; whereupon Quaritch dons an AMP suit and breaches the avatar link unit containing Jake's human body, exposing Jake to Pandora's poisonous atmosphere. In reply, Neytiri kills Quaritch and rescues Jake.
With the exceptions of Jake, Norm, Max and several other scientists, all humans are expelled from Pandora; whereafter Jake is transferred entirely into his avatar with the aid of the Tree.
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