He is best known for his work restoring the Middleton family seat, Middleton Place, outside Charleston, South Carolina following the Civil War. He inherited Middleton Place in 1846 and he pursued the family"s interest in rice culture, carried out agricultural experiments, and further enhanced the gardens with the introduction of azaleas. In addition to Middleton Place, Williams Middleton made his home in town at 1 Meeting Saint, a house he owned between 1855 and 1870.
In 1860 Williams and an older brother signed South Carolina"s Ordinance of Secession that removed the state from the Union, leading to the Civil War.
Only days after the fall of Charleston in 1865, a detachment of Union soldiers from New York occupied Middleton Place. On February 22, 1865, the main house and flanking buildings were ransacked and burned.
He was able to repair the South Flanker sufficiently to make it the post-civil war family home. Williams died in 1883.
In 1886, an earthquake leveled what remained of the Main House and the North Flanker, while the restored South Flanker survived.