John Sebastian Little was born in Jenny Lind in Sebastian County, Arkansas. Little attended Cane Hill College in Washington County, Arkansas for one term.
Little taught school and studied law. He was admitted to the Arkansas bar in 1873. In 1876 he was elected prosecuting attorney of the 12th Judicial District and served in that position until 1882.
Little served in the Arkansas House of Representatives in 1884 and in 1886 was appointed judge in the 12th Judicial Circuit and served for four years.
In 1894 he was elected to fill the unexpired term of U.S. Representative Clifton R. Breckinridge. He served in the US House of Representatives until 1907 when he resigned his seat to take office as Governor of Arkansas.
Little was inaugurated in January of 1907 and shortly thereafter suffered a nervous breakdown which left him unable to execute his official duties.
Little left Arkansas and went to the Texas gulf coast in an effort to rehabilitate. Little never recovered and died in the Arkansas State Hospital for Nervous Disorders. He is buried at the City Cemetery in Greenwood, Arkansas.