With the success of The Beverly Hillbillies and Petticoat Junction, CBS offered producer Paul Henning another half-hour on the schedule — unusually with no pilot required. Lacking the time, he encouraged colleague Jay Sommers to create the series. Sommers used his 1950 radio series, Granby's Green Acres, as the basis for the new series. The 13-episode radio series had starred Gale Gordon and Bea Benaderet (who also sometimes appeared in the TV version) as a big-city family who move to the country.

In pre-production, proposed titles were Country Cousins and The Eddie Albert Show. Green Acres was about Oliver Wendell Douglas (Eddie Albert), an accomplished and erudite New York City attorney, acting on his dream to be a farmer, and Lisa Douglas (Eva Gabor), his glamorous, bejeweled Hungarian wife, dragged unwillingly from the privileged city life she adored to a ramshackle farm. The debut episode was a mockumentary about this big-city attorney's decision to move to a rural area, anchored by former ABC newscaster (and then current host of the CBS game show What's My Line) John Charles Daly. A few weeks after the show's debut, Albert and Gabor returned the favor by appearing on What's My Line as that episode's Mystery Guests, and publicly thanked Daly for helping to launch their series.

After the first episodes the series shifted from a run-of-the-mill rural comedy, developing an absurdist world. Though there were still many episodes that were standard 1960s sitcom fare, the show became notable for its surreal aspects that frequently included satire. They had an appeal to children for the slapstick, silliness, and shtick, though adults were able to appreciate it on a different level.

It was set in the same universe as Henning's other rural television comedy Petticoat Junction, featuring such picturesque towns as Hooterville (mispronounced "Hootersville" by Lisa), Pixley, Crabwell Corners, and Stankwell Falls. As a spin-off, it at times shared some of the same characters. Sometimes Petticoat Junction folks, such as Joe Carson, Newt Kiley, and Floyd Smoot, are seen in "cross-over" episodes and vice versa. Petticoat Junction frequently had crossover storylines with Beverly Hillbillies during 1969-70.

Much of the humor of the series derived from the pragmatic yet short-fused Oliver attempting to make sense of the largely insane world around him. There seemed to be a dual perspective of reality: Oliver versus everyone else. The latter envelops the Hootervillians – and inexplicably Oliver's affluent mother (Eleanor Audley). Mother Douglas lampoons Oliver and mollifies Lisa. There were times when it appeared that Oliver himself lost his bearings, such as when he rented a rooster or climbed a telephone pole to make a call.

The dishonest, oily salesman Mr. Haney (Pat Buttram), who sold Oliver the Green Acres farm, continues to con his easy "mark" in most episodes. Haney, along with young, glib farmhand Eb Dawson (Tom Lester), scatterbrained county agent Hank Kimball (Alvy Moore), and grocer Sam Drucker (Frank Cady), make up the main supporting cast. Eb habitually addressed the Douglases as "Dad" and "Mom", to Oliver's irritation.

General store owner Drucker was a regular on both series, and the first few notes of the Petticoat Junction theme song can usually be heard during the establishing shot of his store. Petticoat Junction regular Betty-Jo Bradley appears in one episode in a short-lived romance with Eb Dawson. Bobbi-Jo appears in the same episode. Kate Bradley appeared in a few of the early episodes trying to help Lisa adapt to country living, most notably giving Lisa the recipe for her infamous "hotscakes". Western film actor Smiley Burnette guested several times as railway engineer Charley Pratt during the 1965 and 1966 seasons, but Burnette's ill health ended the role.

While Drucker is a provincial everyman in Petticoat Junction, his character is bent a bit here (keeping plastic pickles in a barrel to appease "city folk"). Drucker also serves as a newspaper editor and printer; volunteer fireman; constable; justice of the peace; and postmaster. As editor of the Hooterville World Guardian, his headlines were often decades-old. He was slow as postmaster, once delivering a lost 1917 "draft" notice to Fred Ziffel after 51 years, breaking his previous record of delivering a lost 1942 WPA letter to Haney for stealing a shovel, after 26 years. As justice of the peace, he once let his license lapse, unwittingly sending two supporting characters to a premature honeymoon (Ralph Monroe and Hank Kimball). Drucker often is the only townsperson to understand concepts that Oliver Douglas talks about, acting as a go-between, explaining the "city folk" concepts to the townspeople and the motivations and behavior of the Hooterville townspeople to Douglas.

In a slap to government bureaucrats and civil service employees, Alvy Moore plays spacey agricultural agent Kimball who loses his train of thought from one sentence to the next, drawing people into inane conversations, where they have to explain to him what he is saying.

The Douglases' childless elderly neighbors, Fred and Doris Ziffel, "adopted" a pig named Arnold Ziffel as their "son". Arnold understands English, lives indoors, and is pampered. Arnold is an avid TV watcher and a Western fan, he attends school and is mentioned from time to time as the best student in a particular subject. Only Oliver seems cognizant that Arnold is just livestock, although he frequently slips and begins treating him as a boy. Arnold makes regular appearances throughout the series, often visiting the Douglas farm to watch their TV.