A road used in 1690 by Spanish explorer Alonso de Leon crossed this area. Andrew Millican began settlement in 1821. Henry Fanthorp opened his inn in 1834 and a post office in 1835. Kenneth Anderson, the last Vice-President of the Republic of Texas, died at Fanthorp's in 1845; after his burial here, the town was named for him. The county was created and organized in 1846 and named in honor of Jesse Grimes (1788-1866), a signer of the Declaration of Independence and member of Congress of the Republic of Texas. Anderson was made the county seat. During the Civil War, from 1861 to 1865, the county had a gun factory and furnished troops, food, and cotton.