The original Cadzow Castle is believed to have been built in the 12th century on an earlier high status site, as an occasional royal residence for King David I (1124–1153).
Following the forfeiture of their lands for supporting John Balliol, the estate was granted by Robert the Bruce to Walter FitzGilbert de Hambeldon in the early 14th century.
James Hamilton, 3rd Earl of Arran was confined here in April 1566 after four years in Edinburgh Castle, for an alleged plot against Mary, Queen of Scots.
As a result it was destroyed by forces of the Earl of Mar, regent for James VI, in the late 16th century, as retaliation against the Hamiltons for their support of Mary.
A series of excavations, sponsored by Historic Scotland, took place at the castle between 2000 and 2003 and demonstrated that no evidence was found to support an early medieval fortification at the site, nor any large settlement to compete with the traditional medieval settlement of Cadzow now adjacent to the M74 motorway, and in later centuries called the Netherton to distinguish it from the 'Hitoun' of Cadzow.