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Tarzana was originally part of the San Fernando Mission, which was established in 1797 by Spanish settlers and missionaries, who eventually displaced the indigenous population. Later, the area was seized by Mexico and then, following the Treaty of Guadalupe Hidalgo, the United States, at which point the area came to be part of a sequential order of large cattle ranches owned by local elites. Beginning in the 1870s, the area was purchased by investors who transformed it into a large-scale wheat farm operation.

In 1909 the surrounding area was purchased by the Los Angeles Suburban Homes Company. General Harrison Gray Otis, the founder and publisher of the Los Angeles Times, had invested in the company, while also purchasing 550 acres (2.2 km2) in the center of modern-day Tarzana.

In 1915 or 1919, Edgar Rice Burroughs, best known as the author of the Tarzan stories, purchased Otis’s land and built a large home on it, which he called the Tarzana Ranch. Burroughs subdivided and sold the land for residential development, and the neighboring small farms were also converted to residential areas. In 1927 or 1928, local residents renamed the town Tarzana in honor of Burroughs and his famous storybook character.

* Portola Middle School in Tarzana was used as a location for the films Thirteen, The Karate Kid and Akeelah and the Bee.

* Rocko's Modern Life was animated in Tarzana.

* Tarzana Armenian Deli in Tarzana was used as a location for the HBO TV show Six Feet Under. David and Keith have coffee, sandwiches and frank conversation at the eatery.

* Tarzana was the home of John Denver's character (Jerry Landers) in the 1977 film Oh, God!