What followed was a string of seemingly unrelated and short stint jobs. Following a period of drifting and ranch work in Idaho, Burroughs found work at his father's firm in 1899. He married Emma Centennia Hulbert in 1900. In 1904 he left his job and found less regular work, initially in Idaho but soon back in Chicago.

By 1911, after seven years of low wages, he was working as a pencil sharpener wholesaler and began to write fiction. By this time Burroughs and Emma had two children, Joan and Hulbert. During this period, he had copious spare time and he began reading many pulp fiction magazines and claimed:

"...if people were paid for writing rot such as I read in some of those magazines that I could write stories just as rotten. As a matter of fact, although I had never written a story, I knew absolutely that I could write stories just as entertaining and probably a whole lot more so than any I chanced to read in those magazines."

Aiming his work at the 'pulp' magazines then in circulation, his first story "Under the Moons of Mars" was serialized in All-Story magazine in 1912 and earned Burroughs US$400.

Burroughs soon took up writing full-time and by the time the run of Under the Moons of Mars had finished he had completed two novels, including Tarzan of the Apes which was published from October 1912 and went on to become his most successful brand. In 1913, Burroughs and Emma had their third and last child, John Coleman.

Burroughs also wrote popular science fiction/fantasy stories involving Earthly adventurers transported to various planets (notably Barsoom, Burroughs' fictional name for Mars), lost islands, and into the interior of the hollow earth in his Pellucidar stories, as well as westerns and historical romances. Along with All-Story, many of his stories were published in the Argosy Magazine.

Tarzan was a cultural sensation when introduced. Burroughs was determined to capitalize on Tarzan's popularity in every way possible. He planned to exploit Tarzan through several different media including a syndicated Tarzan comic strip, movies and merchandise. Experts in the field advised against this course of action, stating that the different media would just end up competing against each other. Burroughs went ahead, however, and proved the experts wrong—the public wanted Tarzan in whatever fashion he was offered. Tarzan remains one of the most successful fictional characters to this day and is a cultural icon.

In 1923 Burroughs set up his own company, Edgar Rice Burroughs, Inc., and began printing his own books through the 1930s. He divorced Emma in 1934 and married former actress Florence Gilbert Dearholt in 1935, ex-wife of his friend, Ashton Dearholt, adopting the Dearholt's two children. They divorced in 1942. At the time of the attack on Pearl Harbor he was a resident of Hawaii and, despite being in his late sixties, he spent the conflict as a war correspondent. He died in Encino, California on March 19, 1950 having written almost seventy novels.

The town of Tarzana, California was named after Tarzan. In 1919 Burroughs purchased a large ranch north of Los Angeles, California which he named "Tarzana". The citizens of the community that sprang up around the ranch voted to adopt that name when their town was incorporated in 1928.

The Burroughs crater on Mars is named in Burroughs' honor.