Barksdale was born in Smyrna, Tennessee, a son of William Barksdale and Nancy Hervey Lester. He was the younger brother of William Barksdale, the famed Confederate general who was killed at the Battle of Gettysburg during the Civil War. Ethelbert Barksdale moved to Jackson, Mississippi, as a young man and later adopted journalism as a profession. He edited the official journal of the state from 1854–1861 and again from 1876-1883.
Returning to politics in postbellum Mississippi during Reconstruction, Barksdale served as delegate to the Democratic National Conventions in 1860, 1868, 1872, and 1880. He served as chairman of the Democratic State executive committee from 1877-1879.
Barksdale was elected as a Democrat to the Forty-eighth and Forty-ninth Congresses (March 4, 1883 – March 3, 1887). He was an unsuccessful candidate for renomination in 1886, and then engaged in agricultural pursuits in Yazoo County.
He died in Yazoo City, Mississippi, on February 17, 1893, and was interred in Greenwood Cemetery, Jackson, Mississippi.