Port Elizabeth -
Your fastest connection between the Garden Route and Jo'burg or Pretoria is the N10 which joins the N1 in Colesberg. The more beautiful, yet longer route leads through the beautiful Karoo town of Graaff-Reinet on the R75.
On the drive to Middelburg (N9) you should visit the Valley of Desolation and the quaint village of Nieu Bethesda where time seems to be standing still for centuries. The access road is not tarred, though.
In any case, one should take a trip to the Addo Elephant National Park near Port Elizabeth and the Mountain Zebra National Park near Cradock, a small reserve dedicated to the protection of the endangered mountain zebra.