- Jake Sully lives with his newfound family formed on the extrasolar moon Pandora. Once a familiar threat returns to finish what was previously started, Jake must work with Neytiri and the army of the Na'vi race to protect their home.
- Over a decade after the events of the first film, the film begins with Jake Sully narrating his modest and peaceful life as Chief of the Omaticaya Clan and raising a family with his wife Neytiri, which includes his sons Neteyam and Lo'ak and his daughter Tuk, his adopted daughter Kiri (born from Grace Augustine's comatose Na'vi avatar), and a human boy named Spider, the son of Miles Quaritch who was born on Pandora but was unable to be transported to Earth in cryostasis as an infant. While Jake is able to accept Spider as an adopted son, Neytiri is distrustful of him given his human origins. However, all the children mingle and socialize well with each other including Spider, whom Kiri is affectionate with even though he is a human. Spider does not embrace his human heritage and feels more inclined to Na'vi culture and traditions. They lead a normal life until one day they notice a strange star in the night sky. Much to their dismay, they realize its a RDA space-ship with humans returning to Pandora to colonize it, erecting a new main operating base yet again, causing significant destruction to Pandora. Among the new arrivals in the ship is Colonel Quaritch, who has been cloned into a Na'vi body and with his memories uploaded from before his death. As a result, Quaritch is unable to remember his demise at the hands of Jake but is only able to recollect the events in the past and his vengeful mission to eliminate Jake.
To prevent the RDA from exploiting Pandora again, Jake leads a strategic guerrilla operation against the RDA supply lines weakening them. In one of the operations, Lo'ak who disobeys Neteyam and is eager to prove himself as a Na'vi warrior, tries to assist Jake in battle but is wounded. Jake rescues and disciplines him to not endanger his own safety by being reckless. That night, while tending to his wounds, Neytri calmly reminds Jake to be not too hard on Lo'ak, to which Jake expresses his concern as a father for the safety of his children. Meanwhile, the retaliatory strike on the RDA supply lines doesn't sit well with Quaritch who initiates a search mission to kill Jake. During a playful venture, Jake's children along with Spider explore deeper into the rainforest. Unbeknownst to them, Quaritch and his team are in the vicinity exploring the site where Quaritch discovers his human remains. An observant Lo'ak notices their presence and quickly informs Jake. A skirmish ensues and Quaritch's squad captures Jake's children. Jake and Neytiri arrive in time and free most of them, but Spider is taken by Quaritch, who recognizes him as his son. Aboard the ship, the RDA tries to coerce information about Jake from Spider whom refuses. Changing strategy, Quaritch addresses Spider as his son and also to explain more about the Na'vi in exchange for his freedom on his side. Although un-cooperative and unaware of Quaritch's actual mission, Spider teaches Quaritch about Na'vi culture. Quaritch is also successfully able to tame an Ikran flying creature as his vehicle.
Knowing the danger Spider's knowledge of his whereabouts poses to their safety and also to avoid another catastrophe, Jake convinces a reluctant Neytri and his family to banish themselves from the Omaticaya Clan and retreat to the eastern seaboard of Metkayina, a coral reef island whose clan and lifestyle is adapted to Pandora's aquatic habitat. Jake passes on his chief mantle to his successor and leaves together with his family to Metkayina. Once arrived, they are greeted by the clan chief Tonowari and his wife Ronal who is doubtful of them initially. However, Jake explains their situation and they are agreed to stay and given shelter. Even though some tribesmen deride Jake and his children for their genetic human heritage, the family learns the ways of the reef people earning the respect of them. Kiri is fascinated with the aquatic life of Metkayina and develops a spiritual bond with the sea and its creatures, while Lo'ak befriends Tsireya, the daughter of clan chief Tonowari and his wife Ronal.
While adapting to their new environment, Lo'ak gets into a fight with Tsireya's brother Aonung when he makes a crude joke about Kiri and him of their mixed human lineage. Jake admonishes his son for his behavior. At Jake's insistence, Lo'ak returns to apologize to Aonung and his friends. However, they entice him to a trip into the territory of a dangerous sea predator, the akula, and leave him stranded in revenge. The akula tries to attack Lo'ak. However, Lo'ak is saved by and befriends Payakan, a tulkun, an intelligent and pacifistic cetacean species whom the Metkayina consider their spiritual family. Lo'ak is able to communicate with Payakan through signing and removes an old harpoon head from the beast's right fin. Upon his return to Metkayina, Chief Tonowari, who became aware of Aonung's tricking of Lo'ak, asks the former to apologize to Lo'ak, However, Lo'ak takes the blame himself, winning Aonung's friendship. He is also told that Payakan is an outcast among his species. Meanwhile, on a trip to an offshoot of the Tree of Souls, Kiri links with it to meet her mother, but suffers a violent seizure. She is healed by Ronal, but when Jake calls Norm Spellman and Max Patel for help, Quaritch is able to track them to the archipelago where the reef people live. Bringing Spider with him, he commandeers a whaling vessel which is hunting tulkuns to harvest their brain enzymes for creating anti-aging remedies. Quaritch begins to brutally question the indigenous tribes about Jake's location; failing that, he orders the whaling crew to wantonly kill the tulkuns in order to draw Jake out. Lo'ak mentally links with Payakan and learns that the tulkun was cast out because he went against the ways of his species and attacked the whalers who killed his mother.
When the Metkayina learn of the tulkun slaughters, Lo'ak takes off to warn Payakan, followed by his siblings, Tsireya and Aonung. They find Payakan being chased by the whalers, and Lo'ak, Kiri and Tuk are captured by Quaritch. With their children in danger, Jake, Neytiri and the Metkayina set out to confront the humans. Quaritch forces Jake to surrender; but seeing his soul brother imperiled, Payakan attacks the whalers, triggering a fight which kills most of the crew and critically damages the vessel, causing it to sink. Neteyam rescues Lo'ak and Spider, but is fatally shot. Jake faces Quaritch, who uses Kiri as a hostage. When Neytiri does the same with Spider, Quaritch at first denies his son, but desists when Neytiri cuts Spider on the chest.
Jake, Quaritch, Neytiri and Tuk end up trapped inside the sinking vessel. Jake strangles Quaritch into unconsciousness and is rescued by Lo'ak and Payakan, and Kiri summons sea creatures to help her save Neytiri and Tuk. Spider finds and rescues Quaritch, but leaves him due to his cruelty towards the Na'vi and putting his goal to kill Jake's family over being his father and becoming a good man, leading him back to rejoin Jake's family. After Neteyam's funeral, Jake and his family decide to stay with the Metkayina permanently.
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