Mowgli is a man-cub raised by the Indian wolf Raksha and her pack led by Akela ever since he was brought to them as a baby by the black panther Bagheera. Bagheera trains Mowgli to learn the ways of the wolves but Mowgli faces certain challenges and lags behind his wolf siblings, and Bagheera berates him for using human tricks like tool building, instead of learning the ways of the pack.
One day, during the dry season, all the animals in the jungle gather at the Peace Rock to drink the water that remains as part of the Water Truce, a timeout called during a drought that enables all animals to gather at a water hole without fear of being eaten by larger, more predatory animals. The peaceful gathering is disrupted when the fearsome Bengal tiger Shere Khan makes his presence felt. He detects Mowgli's scent amongst the crowd and threatens his life since man is not welcome in the jungle. He holds the scars on his face as proof of man's cruel and destructive nature and issues a warning that when the Water Truce ends and the Peace Rock disappears, he will come for the boy. Thus, a debate and argument arises amongst the members of the wolf pack as to whether or not they should keep Mowgli. But before a general consensus is reached, Mowgli voluntarily decides to leave the jungle for the sake and safety of his pack. Bagheera volunteers to guide him to the human civilization.
However, en-route, Shere Khan ambushes them, injuring Bagheera while Mowgli manages to escape with the help of a herd of water buffaloes. Mowgli, now alone, stumbles upon a thick canopy where he meets Kaa, an enormous Indian python who lures him in with promises of safety and an assurance that she knows who and what Mowgli truly is. Kaa's hypnosis shows Mowgli a vision of his father being killed by Shere Khan and of himself as an abandoned infant being found by Bagheera and also warns of the destructive power of man's "red flower". Having successfully wrapped Mowgli in her coils, Kaa attempts to devour Mowgli, but he is rescued by a sloth bear named Baloo. In exchange for saving Mowgli's life, Baloo tells Mowgli to fetch him honey which is atop a cliff, to which Mowgli unwillingly agrees. Together, they form a close bond and Mowgli decides to stay with Baloo until the winter season arrives.
Back in the jungle, Shere Khan visits the wolf pack looking for the "man-cub." When Akela states that Mowgli has left the pack, Shere Khan kills Akela by throwing him off the cliff. He demands that the boy be handed over to him. Confident that Mowgli will return again, Shere Khan takes over the pack.
When Bagheera returns to fetch Mowgli, he discovers that Mowgli has decided to live with Baloo. Although tension is raised between the three, they all agree to sleep on it until the following morning. At night, Mowgli hears a cry for help and discovers that a baby Indian elephant is trapped in a deep pit. Using his tricks, he fashions a rope to rescue the baby elephant. This forms a bond between Mowgli and the Indian elephants.
Following Bagheera's instructions, Baloo unwillingly confronts Mowgli and lies to him that he never considered him a friend, hoping that Mowgli can change his mind about staying with him. But Mowgli is suddenly abducted by a group of monkeys who take him to an ancient ruined temple and present him to King Louie, a Bornean orangutan-resembling Gigantopithecus who tries to coerce Mowgli into giving up the secret to the elusive and deadly "red flower". Baloo and Bagheera arrive just in time to distract the monkeys and manage to hold them off while Mowgli flees into hiding. King Louie chases Mowgli through the temple, causing it to crumble on top of him. Before Mowgli leaves, King Louie informs him of Akela's demise.
Furious of the fact that Baloo and Bagheera kept him in the dark about Akela’s death, Mowgli decides to return to the jungle and confront Shere Khan to avenge the death of his leader and end his tyranny. But first, Mowgli ventures into the village where the humans live and for the first time, he sees his own kind from afar and gazes at them in amazement. He steals one of the burning torches and heads back to the jungle but accidentally starts a fire. Baloo and Bagheera follow him in close pursuit.
When the news breaks out that a man with the "red flower" is making his way into the jungle, all the animals gather at the Peace Rock. Mowgli confronts Shere Khan, but sees how all the animals of the jungle cower in fear at the sight of the fire he holds. He throws away his torch into the water, allowing Shere Khan to attack him. Bagheera, Baloo and the wolf pack manage to hold him off, thus buying Mowgli enough time to set a trap in the burning jungle. He lures Shere Khan into a dying tree with a fig branch and is able to coax him into stepping on it, causing it to break. Shere Khan falls to his death into the pit of fire below. The Indian elephants later help to extinguish the fire by diverting the river.
Raksha then becomes the new Alpha and leads the wolf pack. Mowgli decides to do things his own way, having at last found a true home in the jungle with the animals, including his friends Baloo and Bagheera.
- Jim Cummings as Winnie the Pooh, Tigger, Buzzie, Ed, and Cheetahto
- Travis Oates as Piglet
- Tom Kenny as Rabbit and SpongeBob SquarePants
- Bud Luckey as Eeyore
- Jeff Bennett as Flap, Zazu, and Petrie
- Jess Harnell as Ziggy
- Baron Davis as Dizzie
- Joe Ochman as Jiminy Cricket
- Veronica Taylor as Ash Ketchum
- Ikue Otani as Pikachu
- Rachael Lillis as Misty and Jessie
- Satomi Korogi as Togepi
- Eric Stuart as Brock and James
- Rob Lowe as Simba
- Gabrielle Union as Nala
- Kevin Schon as Timon
- Ernie Sabella as Pumbaa
- Felix Avitia as Littlefoot
- Anndi McAfee as Cera
- Aria Curzon as Ducky
- Rob Paulsen as Spike and Cheetayta
- Bill Fagerbakke as Patrick Star
- Jeff Bergman as Bugs Bunny and Daffy Duck
- Jim Meskimen as Genie
- Joshua Seth as Taichi "Tai" Kamiya
- Tom Fahn as Agumon
- Michael Reisz as Yamato "Matt" Ishida
- Kirk Thornton as Gabumon
- Colleen O'Shaughnessey as Sora Takenouchi
- Tifanie Christun as Biyomon
- Mona Marshall as Koushiro "Izzy" Izumi
- Jeff Nimoy as Tentomon
- Philece Sampler as Mimi Tachikawa
- Anna Garduno as Palmon
- Michael Lindsay as Joe Kido
- R. Martin Klein as Gomamon
- Wendee Lee as Takeru "T.K." Takaishi
- Laura Summer as Patamon
- Lara Jill Miller as Hikari "Kari" Kamiya
- Edie Mirman as Gatomon
- Bowser Koopa as Himself
- Maddie Blaustein as Meowth
- James Horan as Scar
- Jenifer Lewis as Shenzi
- Cheech Marin as Banzai
- David Lander as Arthur the Vulture
- Michael McKean as Cecil the Vulture
- Keith David as Tublat and Dr. Facilier
- Christopher Plummer as The Grand Duke of Owls
- Neel Sethi as Mowgli
- Bill Murray as Baloo
- Ben Kingsley as Bagheera
- Idris Elba as Shere Khan
- Lupita Nyong'o as Raksha
- Scarlett Johansson as Kaa
- Giancarlo Esposito as Akela
- Christopher Walken as King Louie
- Garry Shandling as Ikki
- Brighton Rose as Grey Brother
- Jon Favreau as Pygmy Hog
- Sam Raimi as Giant Squirrel
- Russell Peters as Rocky the Rhino
- Madeleine Favreau as Raquel the Rhino
- Ritesh Rajan as Mowgli's Father
- Kendrick Reyes as Infant Mowgli
- Sara Arrington as Neelgai
Shere Khan: How many lives is a man cub and a stuffed bear worth?
- The 100 Acre Avatar League, Ash Ketchum, Pikachu, Misty, Togepi, Brock, Simba, Nala, Timon, Pumbaa, Littlefoot, Cera, Ducky, Petrie, Spike, SpongeBob SquarePants, Patrick Star, Bugs Bunny, Daffy Duck, Woody Woodpecker, Ttark, Genie, Terk, Tantor, Louis, Alex, Marty, Melman, Gloria, the Penguins of Madgascar (Skipper, Kolwalski, Private, and Rico), King Julien, Maurice, Mort, Sebastian, the DigiDestined and their Digimon, Bowser, Team Rocket (Jessie, James, and Meowth), Scar, Shenzi, Banzai, Ed, Cheetayta and Cheetahto, Arthur and Cecil, Tublat, Dr. Facilier, and The Grand Duke of Owls will guest star in this film.
- The only reason why the Vultures from the 1967 Disney animated film adaptation of The Jungle Book and Arthur and Cecil from Jungle Cubs guest star in this film is because the vultures featured in the real film were portrayed as minor characters.
- In this film, the Teenage Mutant Ninja Turtles will be opening up a portal to an alternate dimension of Mowgli.
- Like the real film, this film is dedicated in memory of Garry Shandling who died on March 24, 2016.