The 45-year-old lost his battle to motor neuron disease, having first been diagnosed with the illness in 2011.
Van der Westhuizen's health had taken a turn for the worse over the weekend when he was rushed to hospital.
The foundation confirmed the news of his death on Monday and said Van der Westhuizen was sent home from hospital where he died surrounded by family.
The former Springbok captain played 89 Tests for the Springboks between 1993 and 2003.
He scored a then-Springbok record 38 tries and is widely regarded as one of the game’s finest-ever scrumhalves.
Van der Westhuizen played his provincial rugby for the Blue Bulls and the union's CEO, Barend van Graan, expressed his condolences to his children, family and friends:
"If there's one thing we can learn from Joost it was his passion for life. That we will never forget."