Born in Winchester, Virginia, he was noted for writing about that state. He illustrated Virginia life and history in the novels, The Virginia Comedians (1854), and The Wearing of the Gray, a tale of the American Civil War, and more formally in a respected Virginia history. His style was somewhat high-flown. He was the author of The Youth of Jefferson.

Cooke was one of 13 children of John Rogers Cooke and Maria Pendleton Cooke. He was born on the family's plantation, "Amber's Hill," near Winchester, Virginia, in the Shenandoah Valley. At his father’s urging, he studied and practiced law briefly in Richmond. He abandoned that in 1854 after his father’s death, and almost immediately became a successful novelist and prolific short story writer, eventually authoring 31 books and almost 200 published articles and poems. Cooke joined the Richmond Howitzers, a militia artillery unit, in the 1850s, earning the rank of sergeant.

In March and April 1862, Cooke served as an unpaid volunteer aide for Maj. Gen. J.E.B. Stuart in the Confederate cavalry. Cooke was a first cousin of General Stuart's wife, Flora Cooke Stuart. On May 19, 1862, he was formally commissioned as a lieutenant and officially joined Stuart's staff. Cooke participated in the Peninsula Campaign and Stuart's subsequent ride around the Union army of George B. McClellan, later writing a detailed description of the action. During the war, he served Stuart as an aide, ordnance officer, and assistant adjutant general, earning the rank of captain. Following Stuart's death at Yellow Tavern in May 1864, Cooke served on other generals' staffs, eventually rising to the rank of major by the end of the war. In 1863, he wrote the first of several popular biographies of Stonewall Jackson. He also published a novel on Jackson, Surry of Eagle's Nest (1866) as well as a biography of Robert E. Lee, officers that he had personally known.

In 1867, Cooke married Frances Page and settled down three miles north of Boyce, Virginia, to become a prosperous farmer and gardener. He had three children. He died of typhoid fever at his home, "The Briars." Cooke was buried in Old Chapel Cemetery in Millwood, Virginia.

The "John Esten Cooke Award for Southern Fiction" is presented annually to the author of the best historical novel dealing with the South.