There's no best time to visit the Garden Route, although the water and weather are warmest November through March. From mid-December to mid-January, however, the entire Garden Route is unbelievably crowded and hotel prices soar, so try to avoid visiting at this time. Between May and September the weather can be very cold and even rainy. But—and it's a big but—it makes all the more cozy the huge, blazing log fires and large bowls of steaming soup that local hostelries provide. And, of course, there are fewer tourists. Even in these colder months it's rarely cold for more than two or three days at a stretch, after which you'll get a few days of glorious sunshine. Wildflowers bloom along the Garden Route from July to October, the same time as the annual Southern Right whale migration along the coast.
The Little Karoo can be scorchingly hot in summer and bitterly cold at night in winter, but winter days are often warm and sunny. It really doesn't rain much in the Little Karoo.