Born in Culpeper County, Virginia, Walker attended the common schools and served in the American Revolutionary War. He moved to Jessamine County, Kentucky in 1794 and studied law. He was admitted to the bar and commenced practice in Nicholasville, Kentucky in 1799. He served as a commissioner of the Kentucky River Company in 1801.
Walker was a member of the Kentucky State Senate from 1810 to 1814. He was then appointed to the United States Senate to fill the vacancy caused by the resignation of George M. Bibb, and served from August 30, 1814 to February 2, 1815 when a successor was elected. He died in Nicholasville August 19, 1819, and was interred on his estate near there.
George Walker was the brother of David Walker and John Walker and the great uncle of James D. Walker. He was also the uncle of two governors of Florida, Richard Keith Call and David S. Walker. Another nephew John George Walker served as a general in the Confederate Army during the Civil War.