Simon was the son of Ariaen or Adriaan van der Stel an official of the Dutch East India Company (VOC) and Maria Lievens, who married in March 1639 in Batavia.

In 1679, he was appointed "Commander" of the VOC's colony at the Cape of Good Hope, through the growing influence of his relative, Joan Huydecoper van Maarsseveen, a mayor and an amateur botanist.

[5] Simon was involved in making wine in Muiderberg; when he left the country, he handed the vineyards over to Hendrik van Rheede, the former governor of Malabar region and a famous botanist.

In 1685, he was visited by Hendrik van Rheede (with whom he shared in great interest in tropical medicine and botany), and was given Constantia as a reward for 'good and faithful services to the VOC'.

Jean-Jacques Rousseau, in his Discourse on Inequality, refers to Governor Van der Stel by name in a story about a Hottentot raised by the Dutch who chooses to "return to his equals" rather than remain in civilised society.

According to Rousseau, Van der Stel himself raised the "Hottentot" from birth "in the principles of the Christian religion and in the practices of European customs".

Widely known for his development of the South African wine industry, Van der Stel was also the first Cape Governor to be of mixed race-origin, a fact that was largely unacknowledged by the apartheid government.

[11] Journals and records from Van der Stel's travels are kept by the Library of Trinity College Dublin as part of The Fagel Collection.