In 1374, king Robert II granted Craigmillar to Sir Simon Preston. The Preston family remained at Craigmillar for nearly three hundred years, gradually developing and expanding their castle.

The earliest part of the castle is an L-plan tower house. In the 15th century an enclosure wall with round towers at each corner was built around the tower. The walls were topped with machiolations which allowed defenders to drop missiles or fire upon attackers at the base of the walls. In the 16th century a large outer courtyard was formed by the addition of another curtain wall.

Mary Queen of Scots visited the castle on a number of occasions. She was staying at the castle in 1566 when a meeting was held by a group of conspirators including the Earls of Argyll, Huntly and Bothwell, Sir James Balfour and William Maitland of Lethington, to discuss ways of disposing of Mary's husband, Henry, Earl of Darnley. In February 1567, the house Darnley was staying in was blown apart by gunpowder. When his body was discovered amongst the wreckage it was found that he had been strangled.

David Preston was the last member of his family to own the castle. In 1660 he sold Craigmillar to Sir John Gilmour who began an extensive building programme which created a comfortable new residential range on the west side of the inner courtyard. During the 18th century the Gilmours moved to nearby Inch House, and the castle at Craigmillar gradually fell into ruin. In 1813, a walled up skeleton was found in one of the vaults.