Clarke County was created in 1801 by an act of the Georgia General Assembly on December 5. It was named for Revolutionary War hero Elijah Clarke and included that was formerly part of Jackson County. Colonel Clarke played a leading role the 1779 victory at the Battle of Kettle Creek in Wilkes County. The Elijah Clarke Chapter of the Daughters of the American Revolution erected a monument to him in Broad Street in Athens.
As the population of the county grew in the early 19th century, its agricultural and cotton industries prospered. The adjacent plantation harvests flowed through city mills. Manufacturing and textile production operations were the major industries in Clarke County, especially after the railroad reached Athens in 1841. Athens and Clarke County were second only to Savannah and Chatham County in the amount of capital invested in manufacturing in the 1840s.
Two skirmishes were fought in Clarke County in 1864, during the American Civil War, one near Barber's Creek and the other near Mitchell's Road. Athens was occupied by the Union Army on May 29 and a provost-marshal took charge. Formal military occupation of the ended by December 1864, though Union troops remained in the county until early 1866.
In 1801 the Clarke County Commission had selected Watkinsville (now in Oconee County) as the county seat. All county offices, including the courts and jail, moved to Athens when the seat was moved on November 24, 1871. County meetings took place in the old Athens town hall, until a new courthouse was constructed in 1876. The present courthouse was built in 1914.
On February 12, 1875, in response to complaints over the relocation of the county seat to Athens, the state legislature created Oconee County from the southwest portion of Clarke County, making Watkinsville its seat. Clarke County thus lost one-third of its population and three-fifths of its land area.
The position of "commissioner of roads and revenue" was created by the legislature for what are today known as county commissioners. As an extension of the state, the county would conduct welfare and health programs, build and maintain roads, and hold courts of law.
On March 29, 1973, the Georgia legislature increased the number of county commissioners from 3 to 5, also adding a county administrator.
In 1990, the residents voted to unify the city and county governments creating Athens-Clarke County, the second (after Columbus-Muscogee County) unified city-county government in the state of Georgia.