The story begins on the last day of summer. Christopher Robin is unable to tell his friend Winnie-the-Pooh some sad news, and leaves him with the advice, "You're braver than you believe, and stronger than you seem, and smarter than you think," but Pooh doesn't clearly understand. The next morning, Pooh discovers a honey pot with an attached note - however, he cannot read it himself after getting honey all over it. He goes around to his friends Piglet, Tigger, Rabbit and Eeyore, and none of them are able to read it, so they ask Owl for help. From misinterpreting the note and his own romantic imagination of adventure, Owl deduces that Christopher Robin has been taken to a distant, mysterious and dangerous place called "Skull" against his will, to a cave where the monstrous "Skullasaurus" resides. Owl equips the group with a map and sends them into the "Great Unknown" of the Hundred Acre Wood.
During their journey through the Great Unknown, as they are seemingly hunted by the Skullasaurus, the group slowly begins to realize just how helpless they are without Christopher Robin in the outside world. Piglet, Tigger, and Rabbit come to believe they don't have the courage, strength, or intelligence respectively to go on; Piglet is abducted by a swarm of butterflies in a tranquil field, leaving him feeling weak and helpless; Tigger plummets into a deep gorge and is unable to bounce out to safety, causing his friends to fall with him, and Rabbit continuously makes poor leadership decisions following Owl's inaccurate map. Pooh tries to comfort them each with the advice Christopher Robin had given him, but fails due to his inability to remember exactly what he said. When Rabbit finally breaks down, admitting he has no idea where they are going, the group comes to terms with the fact that they are lost and helpless without Christopher Robin, and take shelter in a nearby cave. While everyone is asleep, Pooh laments on getting no closer to finding Christopher Robin.
In the morning, the five realize they'd spent the night in their destination, Skull Cave. As the five enter and split up to search for Christopher Robin on their own after coming across multiple paths, Rabbit fell down a hole, Tigger got scared away by bats, Piglet slipped on rocks, and Eeyore, who was wearing a ceratopsian-like log on his face runs with Piglet sitting on his buttocks. They ran into each other, but got scared away by Pooh, mistaking him as the Skullasaurus. Pooh slides down and gets stuck in a small gap in the cave's crystals, and the four others tumble about to a ledge before finding the "Eye of the Skull" where Christopher Robin supposedly is trapped. Believing Pooh to have been killed by the Skullasaurus, they rise past their fears and doubts and make their way to the Eye of the Skull. Upon seeing his friends' bravery, Pooh excitedly frees himself from the crevasse, only to be trapped in a deep pit where he can find no way out. While there, he realizes that Christopher Robin is still with him in his heart, even when they are not together, just as Christopher had promised. After Piglet, Rabbit, Tigger and Eeyore enter the Eye, they are found by Christopher Robin who has been searching for them as well. He explains he was only at 'school', and the roars of the Skullasaurus they have been plagued by are actually the noises of Pooh's stomach.
Christopher Robin then rescues Pooh from the deep pit. The six exit the Skull Cave, only to discover that from the outside, it and all the other locations on the map weren't nearly as big, nor as scary as they seemed. They return home, and that evening, Christopher Robin says he will return to school the next day. Pooh declares that he will always be waiting for him, and the two happily watch the sunset, knowing they will always have each other in the sanctuary of the Hundred Acre Wood.