Wembley will host South Africa and the Barbarians when the Boks aim to halt a 16-year drought against the invitational side on November 5, 2016.
This match is the third encounter to be confirmed for the Springboks' traditional tour of the Northern Hemisphere at the end of the local season. South Africa will also face England (November 12) and Wales (November 26), with more matches to be added to the tour soon.
The game at Wembley will be the Springboks' first against the Barbarians since 2010, when the composite side recorded their fourth win over South Africa dating back to 1952, when these sides first met.
It will be the Springboks' third visit to Wembley. They first played Wales there in 1998, when the Principality Stadium was being built, and also played Saracens at the famous venue north east of London in a midweek match in 2009.
It will also be the Barbarians' first appearance at Wembley since the Olympic Centenary match against Australia in 2008. The Springboks have played the Baa-baas seven times before, winning three and losing four. Their last win against the invitational side was by 41-31 in Cardiff in 2000.
"The rivalry between the Boks and the Baa-baas goes back many years and has provided many historic occasions," said SARU CEO Jurie Roux.
"To play them at Wembley next year for the first time will add a new chapter – this was the venue for the biggest attendance at the recent Rugby World Cup in England, when close to 90,000 packed the stadium to see Ireland take on Romania.
"It will provide the Springboks will an ideal start to their European tour."