Sir Lionel Frost, portrayed by Hugh Jackman, is an ambitious investigator of mythical creatures who longs to gain entry into an elite society led by his rival, Lord Piggot-Dunceby (Stephen Fry). His fortunes change when he receives a letter confirming the existence of a Sasquatch. In a bid to prove his findings and secure his place in the society, Frost embarks on a journey to the Pacific Northwest, where he encounters the creature, whom he names "Mr. Link" (Zach Galifianakis). To Frost’s surprise, Mr. Link reveals that he was the one who sent the letter, seeking help to locate his relatives, the Yetis, in the Himalayas.
Unbeknownst to Frost, Piggot-Dunceby has sent a ruthless bounty hunter, Willard Stenk (Timothy Olyphant), to eliminate him and prevent any further embarrassments to the society. To reach the Himalayas, Frost turns to his former love, Adelina Fortnight (Zoe Saldana), who possesses a vital map locked away since her late husband’s passing. Their reunion is strained—Adelina resents Frost for missing the funeral and initially rejects his advances. However, a comical break-in at her home leads to a chaotic escape with the map in hand, prompting Adelina to join their expedition under the condition that she accompanies them.
Their journey proves perilous as they face Stenk, leading to an intense shootout. The trio manages to outsmart their pursuer, and as they travel by boat, Adelina encourages Frost to connect with Mr. Link. This bonding moment brings them closer, with Mr. Link adopting the name "Susan" after a friendly prospector he once knew. However, their camaraderie is interrupted when Stenk ambushes them again, culminating in a series of chaotic skirmishes aboard the ship, where they manage to lock him away temporarily.
Upon reaching the foothills of the Himalayas, the trio meets the Yeti Queen (Emma Thompson), who reveals the Yetis' deep-seated distrust of humans, including Susan. Captured and thrown into a pit, the friends devise a daring escape. After confrontations with the guards, they make their way towards an ice bridge where Piggot-Dunceby and Stenk await. In a climactic confrontation, Frost stands up for Susan, declaring his belief in Susan's humanity over the prejudices of Piggot-Dunceby and his henchman, Mr. Collick (Matt Lucas).
As tensions rise, Piggot-Dunceby attempts to shatter the ice bridge, resulting in a disastrous fall for him and his companion, while Frost and his allies narrowly escape. Stenk, who finds himself alone on the other side, challenges Frost, leading to a comedic exchange of slaps while clinging to the edge of the ice. Together, they finally rid themselves of Stenk, sealing his fate with a falling icicle.
Triumphant yet reflective, Frost recruits Susan as his new partner in investigation. Shortly after returning home, Adelina informs Frost of her intention to pursue her own adventures, yet they share a tender moment of mutual acknowledgment regarding their feelings. As they embark on their next case to unearth the lost city of Atlantis, the closing credits showcase maps and mementos from their many new adventures together.
