The series was developed as a vehicle for teenage star Patty Duke, who had won an Academy Award the previous year.

Patty Lane (Duke) is a normal, chatty, rambunctious teenager who (according to the theme song lyrics) lives in the Brooklyn Heights section of New York City.

Her father, Martin Lane (William Schallert), is the managing editor of the New York Daily Chronicle; Patty affectionately addresses him as "Poppo."

Since the widowed Kenneth is often away as a foreign correspondent for the Chronicle, Cathy moves to the United States to live with Patty's family – which also includes her mother Natalie (Jean Byron) and brother Ross (Paul O'Keefe) – and to attend Brooklyn Heights High School with Patty and her boyfriend Richard (Eddie Applegate).

While the girls are physically identical, their style, tastes and attitudes are nearly opposite, which is responsible for some of the comedic situations on the show.

The remarkable physical resemblance that Patty and Cathy share is explained by the fact that their fathers are identical twins.

Patty and Cathy have an additional identical cousin, Southern belle Betsy (also played by Duke), featured in the season two episode "The Perfect Hostess".

In the series' unaired pilot episode, Mark Miller and Charles Herbert played Martin and Ross Lane, respectively.

During this time, he noticed that Duke had two distinct sides to her personality (later in life she would be diagnosed as manic-depressive)[3]: 287  Two years earlier, the Walt Disney comedy The Parent Trap with Hayley Mills as identical twins, had been a major success.

Several differences in the pilot included the series being set in San Francisco; and Mark Miller and Charles Herbert portraying Martin and Ross Lane, respectively.

Schallert was hired after reading for producers, and reuniting him with his Byron, his co-star from The Many Loves of Dobie Gillis (which had ended the season before).

With the move came new sets and new exterior shots, the latter of which seemed to place the home in an unnamed suburban neighborhood instead of Brooklyn Heights.

He was able to direct one of the final season three episodes – in which Patty and Richard contemplate getting married – which Duke said in hindsight "was not a good idea.

The show's theme song, "Cousins,"[11] which has since been parodied many times over in pop culture (including Rocko's Modern Life where it was parodied as the theme song to "The Bloaty and Squirmy Show"), illustrates the two girls' differences: "...where Cathy adores the minuet, the Ballet Russe and crêpes Suzette, our Patty loves her rock 'n' roll, a hot dog makes her lose control..." The song was performed by a five-voice vocal ensemble called "The Skip-Jacks," a vocal group that worked with jazz musician Don Elliott and recorded numerous Little Golden Records in the sixties.

Repeats of The Patty Duke Show entered local markets as early as September 1966, days after exiting ABC prime time.

A new generation of viewers was introduced to the series by Nick at Nite cable, broadcasting a lengthy five-year prime time run from September 19, 1988, to August 30, 1993.

Reruns of The Patty Duke Show were seen on Antenna TV from 2013 until 2015 as part of that channel's regular programming schedule.

In the film, Patty and Richard married after graduating high school, and had a son Michael (Alain Goulem) before an amicable divorce after nearly 27 years of marriage.