Probably the most popular Cape Town Safari route is to drive along the beautiful southern coast of South Africa between Cape Town and Port Elizabeth, and go on safari in one of the malaria-free game reserves of the Eastern Cape.
The total distance by road from Cape Town to Port Elizabeth is about 750 km, and the reserves are then between an hour to 2 hours drive further from Port Elizabeth, so we certainly don't recommend trying to drive this in a day.
Most visitors take a couple of days to drive along the Garden Route - the Garden Route is beautiful, and it is definitely a worthwhile addition to any holiday itinerary. If time is precious, however, you can fly between Cape Town and Port Elizabeth, which takes just over an hour. When you land at Port Elizabeth Airport, you can then either hire a car from the airport and drive yourself to your chosen reserve, or else a transfer can be arranged.