"At this stage we're viewing the series as a one-Test series, that's how important the match in Durban is. It's all or nothing on June 20," de Villiers told the Sunday Times in South Africa.
"It's very difficult to come back if you're 1-0 down. That will be a massive examination for us, and our focus is on that game at the moment - we're not even thinking about Tests two and three."
After missing the last two World Cup campaigns through injury, de Villiers is keen to have a clean bill of health as the Boks try to avenge their 2-1 series defeat by the Lions 12 years ago.
But while he has recovered from his groin problems, de Villiers was recently struck by a recurring back problem
"I came through 30 minutes against Namibia, but last week I woke up with a stiff and sore back. The same thing happened last year before the Wales Test and I found it difficult to walk," he said.