Bob and Margaret was the second adult animated series after Family Dog (a failed CBS sitcom) to be produced by Nelvana, who originally had made their name in children's properties, such as Grossology, Stickin' Around, Maggie and the Ferocious Beast, and Eek! The Cat. The series also served as Nelvana's first adult animated project since 1983's Rock & Rule. Most of the production was done in the Toronto-based Nelvana studio, including people who worked on other Nelvana shows, such as Clone High, The Magic School Bus, and Tales from the Cryptkeeper, with the character design supervisor being Todd Kauffman, who would later be well-known for his work on shows like 6teen, Yin Yang Yo!, and Total Drama, and would later be known for creating Sidekick, Grojband, and Looped. Sound editor Ryan Araki would later do audio work for The Bob's Burgers Movie.
The writing and voice acting was mainly done in the UK. Snowden and Fine reviewed storyboards, did voice direction, wrote scripts, and so on from their own quarters in London and Toronto (the latter at Nelvana). Most characters were done by London actors, while there were some from Toronto as well, mainly in season one.
Following the success of Bob's Birthday, creators David Fine and Alice Snowden were brought on board by different companies for show opportunities. One of those parties was Universal Pictures, but the two declined the offer, as Universal was concerned about the show being "too British". Universal wanted Bob and Margaret to move to the United States of America, or have American friends, but that's when Canadian studio Nelvana swooped in. They paid for 75% of the show's budget, with the UK's Channel 4, who did the Bob's Birthday short, supplying the rest.