Giles County is named after William Branch Giles, a senator from Virginia who sponsored the admission of Tennessee as the 16th state into the Union. He also sponsored the building of the city and courthouse, which has burned four times. The current courthouse was built in 1909. One of Giles County's local heroes is James McCallum, who served as grandmaster of the Tennessee Masons, a member of the Confederate Congress, and mayor. He lived in Giles County for 70 years.
Until Maury County was established in November 1807, the area of the future Giles County was part of Williamson County. Two years after the formation of Maury County, Giles County was created from southern Maury County on November 14, 1809, by an act of the state legislature. Nearly half of the new county lay in Chickasaw territory until September 1816.