The broadcaster and actor will play the secret service boss when the show makes its comeback next year for a new generation of young viewers.
Alexander Armstrong, who is lined up to play the show’s title character, will be reunited with his co-star on BBC1 quiz Pointless as Richard Osman has a guest role.
Osman will play boffin Professor Strontium Jellyfishowitz - a faceless jellyfish in a motorised fish tank - who heads the world’s scientists.
The programme is to return after an absence of more than 20 years with a series on CBBC.
Fry’s character is the boss of Danger Mouse and his sidekick Penfold (Kevin Eldon), and also has a reputation as the world’s dirtiest croquet player and chairs the Willesden Green Amateur Flower Arranging and Operatic Society.
Also joining the cast are Kayvan Novak - known for Channel 4’s Facejacker - who will play a number of different characters, while Ed Gaughan will play amphibious villain Baron Greenback.
Talking about his new role, Osman said: “As a lifelong fan of the show and a slightly more recent fan of Alexander Armstrong, I could not be more delighted to be playing my own small part in this incredible new version of Danger Mouse.”