The new service will operate three times a week from December 15, 2016 to March 20, 2017.
The airline will use its refurbished A330 fleet.
Tickets will be priced from £699 (new economy) and £949 (new premium) return and will go on sale in December.
Christoph Debus, chief airlines and hotels officer for Thomas Cook, said: “Cape Town really is a ‘wow’ destination for our customers.
"It builds on our Cancun, Cuba and Goa long haul routes from Gatwick which are really popular and more broadly comes on top of new services from Manchester to New York and Miami this year, and to Los Angeles and Boston next year.
“Coupled with our premium class cabin and new long haul economy standard, our seat-only service, is proving hugely popular as customers become aware that they can get the great Thomas Cook quality to some amazing long haul destinations."
Guy Stephenson, chief commercial officer at Gatwick airport, said: "Cape Town is a spectacular destination to add to Thomas Cook Airlines’ growing network of long haul routes from Gatwick.
"The airline’s existing long haul flights to the Cuba, Mexico and India are an important part of Gatwick’s rapidly growing long haul network, which now boasts over 40 destinations on five continents.”