He left school at the age of 17 to become a teacher himself, while he continued his studies at a number of institutions including Cooperstown Seminary, where he first read the works of William Wordsworth and Ralph Waldo Emerson, both of whom would become lifelong influences through their focus on nature and its effect on the spirit.

Three years later he married Ursula North, while continuing his teaching career with an eye toward becoming a published author, which along with her more prudish attitude to sexuality strained his relations with her. The couple struggled financially and were not able to set up their own household until 1859.

The next year he finally broke through as a writer, when the Atlantic Monthly, then a fairly new publication, accepted his essay "Expression" (Editor James Russell Lowell found it so similar to Emerson's work that he initially thought Burroughs had plagiarized his longtime acquaintance). A short poem, "Waiting", also attracted some attention.

With the onset of the Civil War, and his growing ability to live off his writing, he began to spend more time away from his home in upstate New York and in the literary scenes of New York and later Washington. In 1864, he accepted a position as a clerk at the Treasury, where he would eventually become a bank examiner.

He continued to publish, and grew interested in the poetry of Walt Whitman, whom he frequently defended in literary arguments and later met during a period when Burroughs and his wife were separated. He would become a life-long friend of the Burroughses, and vainly attempted to reconcile the two.

Whitman encouraged Burroughs to develop his nature writing, and Burroughs' work in turn improved Whitman's own perceptions of nature. In 1867, Burroughs published Notes on Walt Whitman as Poet and Person, the first biography and critical work on the poet, extensively revised and edited by Whitman himself.

Four years later, Wake-Robin was published and became a huge bestseller. As industrialism was solidifying its grasp, readers wanted to be reminded that some of the nature they had never sufficiently appreciated was still around. Burroughs had found his niche, and created the nature essay.Later he was invited to be a leader of a College nature club which eventually became known as "The Wake Robin Club".

In 1874, he bought a small farm in West Park, NY (now part of the Town of Esopus), and devoted himself completely to his writing. Later, he bought some land nearby and in the fall of 1894, began work with his son on an Adirondack-style cabin that would be called "Slabsides". At Slabsides he wrote, grew a large field of celery, and entertained visitors, including students from local Vassar College.

Burroughs also renovated an old farmhouse near his birthplace and called it "Woodchuck Lodge." This became his summer residence until his death.

He continued to write books of nature essays, some published in periodicals of the time as well, and sell well. Some of the best came out of trips back to his native Catskills. "The Southern Catskills" (sometimes "The Heart of the Southern Catskills") was the first recorded ascent, in the late 1880s, of Slide Mountain, only recently established as the highest in the region. He had tried to summit the mountain on several previous occasions; when he at last did so he wrote of the view:

The works of man dwindle, and the original features of the huge globe come out. Every single object or point is dwarfed; the valley of the Hudson is only a wrinkle in the earth's surface. You discover with a feeling of surprise that the great thing is the earth itself, which stretches away on every hand so far beyond your ken. Some of these words are on a plaque commemorating Burroughs at the mountain's summit, on a rock outcrop later named Burroughs Ledge. Slide and neighboring Cornell and Wittenberg mountains, which he also climbed on that outing, have been collectively named the Burroughs Range, as has the hiking trail built over it.

Other Catskill essays told, with as much wry humor as awestruck reverence, of fly fishing for trout, of hikes over Peekamoose Mountain and Mill Brook Ridge, of rafting down the East Branch of the Delaware River. It is for these that he is still celebrated in the region today, and chiefly known, although he traveled extensively and wrote about many other regions and countries, as well as commenting on natural-science controversies of the day such as the relatively new theory of natural selection. He also entertained philosophical and literary questions as well, and wrote another book about Whitman in 1896, five years after the poet's death. Ultimately his writing helped persuade the literary establishment of Whitman's virtues.

Burroughs accompanied many personalities of the time in his later years, including Theodore Roosevelt, John Muir, Henry Ford (who gave him a car, one of the first in the Hudson Valley), Harvey Firestone, and Thomas Edison. Most notably, in 1899, he participated in E. H. Harriman's expedition to Alaska.

In 1901, Burroughs met Clara Barrus, nearly half his age, the love of his life and ultimately his literary executrix. She moved into his house after Ursula died in 1917.

He died on a train returning from California. He was buried on what was to be his 84th birthday, in Roxbury, at the foot of the rock he had played on as a child.

Burroughs was a popular and highly regarded author in his day. An award for nature writing has been named for him, along with 11 U.S. schools, including public middle schools in Milwaukee, Wisconsin and Los Angeles, California, a public high school in Burbank, California, and a private secondary school in St. Louis, Missouri.

Many of Burroughs' essays first appeared in popular magazines. Twenty-three volumes of these essays, published between 1871 and 1922, are usually considered to make up the "Writings of John Burroughs" of which collected editions have been offered in numbered sets by at least three publishers.

He is best-known for his observations on birds, flowers and rural scenes, but his essays topics also range to religion and literature. Burroughs was a staunch defender of Whitman and Henry David Thoreau, who were then unpopular because of their perceived literary excesses.