Nienaber was assistant coach with the Springboks when they won the 2019 World Cup in Japan and was elevated to the top job when Rassie Erasmus (50) returned to his director of rugby position after the tournament.
The pair are long-time friends and worked together in South Africa and at Irish side Munster.
"The last few years have been the highlight of my coaching career and it’s with a heavy heart that I’m finishing up my time with the Springboks and leaving the country for personal reasons," Nienaber said in a news release from South African Rugby on Saturday.
"The decision is made and that’s firmly behind me now. My sole focus is on seeing the Springboks defend the Rugby World Cup title this year.
"I will continue to channel all my energy into ensuring that we leave no stone unturned to achieve that."
Leinster head coach Leo Cullen (45) is looking forward to working alongside the South African when Lancaster leaves for Racing 92 at the end of the current season.
"Jacques is a world class coach with a winning track record at the very highest level of the game, and we’re all looking forward to learning from him over the coming seasons," Cullen told his club’s website.
"With the addition of the South African teams to the United Rugby Championship and the Champions Cup, Jacques’ in-depth knowledge and experience of working with the Springboks will be a great addition to the group."
SA Rugby CEO Rian Oberholzer said there was no chance of Erasmus following Nienaber out of the door soon.
"We will confirm a successor in the title role of Springbok coach in due course – that planning will go on in the background, but Rassie Erasmus’ services are locked in to the end of 2025 at the very least," he said.
South Africa have been drawn with Ireland and Scotland in their pool at the World Cup, which starts on September 8th. Should they make it out of their group, they will likely face France or New Zealand in the quarter-finals.
