Since Lord Garmadon’s disappearance from the Underworld, Ninjago has been at peace, but the young ninja have grown lazy. While Garmadon lurks in the shadows, waiting for the right moment to strike, the ninja meet his young son, Lloyd, who carelessly unleashes a fearsome new enemy upon Ninjago – the ancient tribes of the Serpentine. The leader of the Serpentine, Pythor, hatches an evil plan to bring back the legendary, all-consuming snake, the Great Devourer.

Peace has returned to Ninjago, and the Ninja have grown complacent. They are abruptly called back into action, though, when they receive reports that Lord Garmadon has returned. However, this just turns out to be his young son, Lloyd Montgomery Garmadon, up to mischief. The Ninja hold a tournament to decide between themselves who is destined to become the legendary ‘’Green Ninja’’. Meanwhile, Lloyd fortuitously discovers the Tomb of the Hypnobrai Tribe of the Serpentine and releases them.

The Ninja have returned to training, preparing for the looming threat of the Serpentine. A mysterious falcon leads Zane to a treehouse, being built for Lloyd by the Hypnobrai. The rest of the Ninja arrive, confronting Lloyd and the snakes. However, they return to their Monastery to find it in ruins, after it was left unguarded. Zane, with the help of the Falcon again, soon discovers them a new home – a ship called the ‘’Destiny’s Bounty’’.

Lloyd, bitter after he was cast out by the Hypnobrai, releases the Fangpyre Tribe from their tomb. Back on the Destiny’s Bounty, the Ninja begin to clean and prepare it to be their new headquarters and are visited by Jay’s parents – Ed and Edna. The Fangpyre attack the junkyard owned by Jay’s parents, and the Ninja encounter the Fangpyre for the first time. They must rush to save Ed and Edna from their transforming venom.

After the Fangpyres join forces with the Hypnobrai, Lloyd releases Pythor – the last of the Anacondrai Tribe. Pythor, pretending to be his friend, steals a map from him that shows where the two remaining snakes tribes dwell. Sensei Wu then takes Lloyd under his wing.

Lloyd moves in and plays pranks on the Ninja (including turning Zane's ninja suit pink) to trick them into fighting amongst themselves. Wu encourages him, hoping to teach the Ninja a lesson about unity. Meanwhile, Pythor releases the Venomari and Constrictai Tribes from their tombs and plans to unite them under his leadership. The Ninja infiltrate their meeting and, inspired by Lloyd's pranks, manipulate the tribes into fighting each other. Pythor discovers them, and they are nearly captured, but Zane's pink suit enables them to hide and escape. 

Pythor finds the ancient Serpentine city of Ouroboros, and declares himself to be the Snake King, the destined leader who will reawaken The Great Devourer – an ancient, seemingly immortal beast who will consume all of Ninjago. Lloyd, who witnesses all this, is discovered and imprisoned. The Ninja, now wearing new ZX suits, attempt to rescue him, but are nearly captured themselves, only to be saved by the mysterious Samurai X, who Kai discovers to be Nya.

When the four Ninja follow the mysterious falcon into the woods, they stumble on a hidden workshop where Zane learns the secret about his past; he is a nindroid designed to 'protect those who cannot protect themselves', as said by his deceased father. The discovery of his past allows Zane to unlock his true potential. Meanwhile, Master Wu travels to the realm of madness to find Lord Garmadon.

Jay and Nya have to cut their first date in the Mega-Monster Amusement Park short, as the Serpentine arrive to retrieve the first of the four Fang Blades needed to awaken the Great Devourer. To make matters worse, Jay pricks his hand on the fang of a skeletal Fangpyre, triggering a transformation. The other three ninja fail to stop Pythor and the Serpentine from retrieving the first Fangblade. Jay unlocks his true potential, saving Nya and overcoming the transformation, while Nya reveals her Samurai X identity. In the Realm of Madness.

The four Ninja go undercover as a dance troupe and enter a talent contest in their quest to win "The Blade Cup", in which one of the Fangblades is hidden, taken from its tomb by Clutch Powers. During this, Cole meets his father, the leader of one particularly famous dance troupe, the “Royal Blacksmiths” who, if anything, is bossier than Sensei Wu. At one point, Cole contemplates stealing the cup, but is berated by his father and decides to make him proud by performing and winning the cup.

The Ninja are suspicious when Lord Garmadon moves in to help search for his missing son, but realize they have to work together in their attempt to rescue Lloyd from the Serpentine while they dig for the third Fangblade in the heart of the Fire Temple. Kai, after being held back by his ambition to become the Green Ninja, reaches his true potential and rescues Lloyd. It is also revealed, though Kai's own realization, that Lloyd is the destined Green Ninja. This causes grief to both Wu and Garmadon.

At a suggestion from Lloyd to steal back the three Fangblades as Pythor goes for the fourth, the Ninja and Sensei Wu try to infiltrate the inner sanctum of the Serpentine and walk right into a trap. When Lloyd's rescue mission does not go as planned, there is only one person who can help them, namely Lord Garmadon. In the nick of time,  
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Upon arriving at Torchfire Mountain, the only place where the Fangblades can be destroyed, Pythor reveals himself and steals the blades back, leaving the Ninja to die. Luckily, Nya saves them. The four ninja, with Wu, Nya as Samurai X and Lloyd, haste to the lost City of Ouroboros to try to stop Pythor from awaking the Great Devourer, but it is a race against time. After a battle on a Serpentine Truck-fortress.

Disaster threatens as the Ninja must fight to defeat the all consuming Great Devourer in a desperate attempt to save Ninjago. In the end, only Lord Garmadon, using the Four Golden Weapons with the elements of fire, ice, lightning, and earth, can destroy the Great Devourer. He manages to kill the snake and Wu is shown to have survived, but Lord Garmadon vanishes with the Weapons and Lloyd must accept the fact that he must face him one day.