Writing in sarugbymag.co.za, de Villiers said the strain of living in a bio-bubble, will be felt as the tour reached its climax.
"Competing in an empty stadium – bereft of fans and the energy that so often inspires game-winning feats – will demand yet another shift in mindset," he said.
Lions tours were especially affected because of the hype and energy around them, especially when so many fans travelled from Britain and Ireland to follow the tour.
As a result, the 2021 tour would be notable for not living up to previous tours in that respect.
"When I look back on my time with the Springboks, I remember what it was like to play Test matches at home. You do take a lot of energy from what is a unique South African crowd," he said.
De Villiers first experienced what it was like to play the Lions at Durban in 2009.
"It was a different experience altogether. There was so much media hype before that first Test at Kings Park. The travelling fans were everywhere. You couldn't walk out the hotel door or down the road to the mall without seeing someone wearing a Lions jersey," he said.
There was also the shock when walking out onto the ground to play.
"There we were, expecting home-ground advantage in one of the biggest games of our lives, but the travelling support was so significant that it effectively cancelled out the local support.
"Right away, we had to make an adjustment. We took it as part of the challenge. The Lions fans were making an almighty racket, and we felt we had to silence them. We did exactly that when we scored early on. We eventually went on to win the game.
"When we got to Loftus Versfeld for the second Test, the Lions were ready for us. We had to fight for every inch in that game. In the end, the South African supports in the crowd inspired us to finish strongly and win the series," he said.
But coping with the Lions' fans wouldn't be an issue, although that could be both a positive and a negative, de Villiers said.
The Springboks wouldn't have to cope with the fans, but at the same time, they wouldn't be able to draw on the energy a full house provided.
"Players are used to feeding off that energy. When lockdown lifted in England last August, the clubs struggled to adapt to a game without fans. More recently, after the fans' return to the stadiums, the clubs have produced some outstanding rugby."
There was a reason for that, he said.
"Generally speaking, you do, as a player, feel a greater sense of responsibility when you're playing in front of an expectant crowd," he said.
Plans will have been put in place by both sides to cope with the surreal situation.
"The team that best embraces life in a bubble, and builds a strong team culture, will go into the Tests with an edge. The side that best prepares for the unique challenge of playing in quiet, empty stadiums will be best placed to win the series," he said.