Mister Ed can be traced back to a series of stories about a talking horse of the same name written by Walter Brooks. Arthur Lubin, director of five Francis the Talking Mule movies from 1949 to 1955, had read the stories and decided to adapt the idea for television. With financing from George Burns, a pilot was made titled The Wonderful World of Wilbur Pope. It starred Scott McKay as lawyer Wilbur Pope, Sandra White as his wife Carlotta, and Allan "Rocky" Lane in an uncredited role as the voice of Mister Ed. The pilot was not picked up, but the idea survived.

The formation of Filmways Television Productions gave new life to the show. Al Simon, president of the new company, took a look at the pilot and considered it a diamond in the rough. He felt that although the pilot was severely lacking, the concept was a potential hit. Filmways collaborated with George Burns and Arthur Lubin to form "The Mister Ed Company" and the project moved forward, but without McKay and White. Alan Young was selected to play Wilbur Post, the architect blessed (and at times cursed) with a talking horse. Wilbur's frustrated yet loving wife Carol would be played Connie Hines. The sitcom would revolve around the silly situations created by Ed's desire to do things people do and Wilbur's inability to control and explain his horse's behavior, which others assume is his own. Wilbur's dilemmas would be compounded by Ed's refusal to speak to no one else but him. Mister Ed had solid backing and a promising premise, but what it really need now was a time slot.

Filmways' enthusiasm about the show was not shared by the three networks, which turned them down flat. The company learned the automobile manufacturer Studebaker may be interested in helping finance a syndication deal. A short presentation was prepared and shown at a dealership meeting in Chicago. It was a big success. Each dealership bought a time slot at their respective markets and Mister Ed was cleared for takeoff (see Ed and Studebaker for more).

Production began in October 1960. Joining Young, Hines, and Lane on the set were Hollywood veteran Larry Keating as the grouchy, business minded neighbor Roger Addison and Edna Skinner as his wife Kay. Last but not least was the former Bamboo Harvester as Mister Ed the clever, talented, smart-alecky talking horse. The show spent the first year in syndication, but when Studebaker could not fully finance a second season CBS added it to its Sunday night lineup. Although a talking horse show could be perceived as kiddy fare, those adults who gave it a chance found there were plenty of laughs for them as well. Mister Ed became a hit (even winning a Golden Globe) and remained one despite the changes ahead. In season four following Keating's death, Wilbur's former commanding officer, retired Colonel Gordon Kirkwood and his wife Winnie (Leon Ames and Florence MacMichael) replaced the Addisons. The show went on without neighbors when the Kirkwoods were dropped at the end of season five. Then midway through season six, the show's run came to an abrupt end.

The final original episode of Mister Ed aired on February 6, 1966. In his autobiography, Alan Young recalls the cast was preparing for a script reading when word of the cancellation came down. Everyone was stunned. Mister Ed was a hit so no one was prepared for its sudden demise. Young speculates that a new program director at CBS felt the need make a change. Others cite questionable scheduling decisions, including the lack of a consistent time slot (the show was given a new slot at the end of each season). Regardless, Mister Ed's destiny seemed to be that of an old soldier - it would just fade away from the public's consciousness.

Although Mister Ed has been in syndication since its cancellation, the show experienced a return to glory when the show began airing on Nick at Nite in the 80s. A Mister Ed revival occurred as viewers from the 60s rediscovered the show while new fans discovered it for the first time. Today, TV Land has brought Ed, Wilbur, and the gang into the 21st century where new generations have been introduced to this charmingly absurd show about a man and his talking horse.

• 1963 Golden Globes - Best TV Show (co-winner; tied with The Defenders and The Dick Powell Show)
• 1997 - The episode Leo Durocher Meets Mister Ed placed #73 on the TV Guide's list of The 100 Greatest Episodes of All Time.
• 2003 TV Land Awards - Favorite Pet/Human Relationship - Mister Ed and Wilbur Post (winner)