de Villiers said he could see the value of the Springboks playing in the European competition. But, he was also concerned about the impact of their rivalry on New Zealand and Australia.
Reasons for making the change would have to be more than commercial, he said.
De Villiers made his comments in a panel discussion in South Africa with former Scotland lock Jim Hamilton.
If a transfer to the northern competition occurred, it could be dangerous for South African rugby, de Villiers said.
"But there could be a perfect situation for South African rugby as well, if we enter [the] Six Nations and we are still involved in the Rugby Championship. Being South Africa…I think that could be a perfect scenario."
While the Six Nations had changed through the years from a four-nation to a five-nation contest and the Six Nations, there was no reason why it couldn't change again, he said.
"The question will always be, what is the reason for the change? If it is only commercially driven, I suppose it probably will happen," he said.
Hamilton said he hoped it wouldn't happen.
"I am a complete traditionalist and romantic around the Six Nations. And, as much as I love South Africa, I don't want to see them in the Six Nations. But I do think it is going to happen," he said.
With the way South Africa was now involved in European club rugby, the different dynamics suggested a change would be inevitable.
Hamilton said, "I can't get my head around the Six Nations being any different with the European games, and going to Rome, Cardiff, Edinburgh, Paris and London…these fantastic rugby places. Not that South Africa isn't, but I can't get my head around it."
However, one sticking point Hamilton raised was what impact a move north would have on the future of British & Irish Lions tours to South Africa. It would take the romance out of tours if the Springboks played the four home nations every year.
De Villiers said that was a point for consideration.
"I would be so saddened to see the Lions not happen.
"A Lions tour, as a South African, is one of the most special things ever. Even last year, I was fortunate to be at all three Test matches, even without a crowd, it is something that we can never let go of," he said.