The film opens with a pickpocketing monkey named Babi who tells his nephew how he met the Buddies. Their great uncle, Digger was the partner of an archaeologist, Thomas Howard, who retrieved one half of a dial which would lead to Queen Cleocatra's tomb. He never found the other half and retired. The scene then switches to present Fernfield where Thomas is giving his grandson, Pete, a tour of the Egyptian exhibit. The Buddies are also there. Pete stays behind with Thomas who gives his dog, MudBud, Digger's bandanna. A British archaeologist, Phillip Wellington along with his cat, Ubasti, meets Thomas in his office and reveals to have the other half of the dial, and insists on bringing him and Pete along for the ride, but refuses to bring along MudBud due to certain allergies. Fortunately, the Buddies stowaway in Phillip's DC-3 Douglas airliner via a box of TNT.
In the climax, Phillip is revealed to be a kleptomaniacal grave robber who challenges Thomas to a fierce duel after Ubasti is turned to stone after wearing Cleocatra's collar, he escapes with it but is captured by the Nomads, tied to a camel and (per request) is placed under the custody of the British embassy. Thomas and Pete are declared national heroes along with the Buddies and the collar is put on permanent display in the museum in Fernfield.
- Richard Riehle as Thomas Howard
- Edward Herrmann as Dr. Phillip Wellington
- Mason Cook as Pete Howard
- Adam Alexi-Malle as Amir Sabbagh
- Mo Gallini as Tarik
- Christopher Maleki as Seti
- Ranya Jaber as Farah
- Anna Primiani as Cleopatra
- Skyler Gisondo as B-Dawg
- Charles Henry Wyson as Buddha
- Ty Panitz as MudBud
- Tucker Albrizzi as Budderball
- Genevieve Hannelius as RoseBud
- Maulik Pancholy as Babi, a mischievous pick-pocketing Capuchin Monkey. He helps the Buddies look for Cammy's parents.
- Kaitlyn Maher as Cammy, a baby Dromedary camel. She goes with the Buddies in order to look for her parents.
- Elaine Hendrix as Ubasti, a Sphynx cat and the primary antagonist
- Bonnie Somerville as Mala, a dromedary and Cammy's mother.
- Ryan Stiles as Slither, a mystical cobra.
- Tim Conway as Deputy Sniffer
- This is Skyler Gisondo's final voice role as B-Dawg, as he will later be replaced by Cooper Roth for Super Buddies.
- This is the last film that Disney released under the name "Walt Disney Pictures". Starting with The Muppets, only "Disney" is used in the logo.
- Roger, one of the dogs in the film, went on to star in several white supremacist films and has appeared in advertisements the Trump campaign ran on the Stormfront website.