Tributes began to flow as news spread of the death of the man who played a pivotal role in South Africa's Rugby World Cup win in 1995.
Van der Westhuizen played 89 Tests for the Springboks between 1993 and 2003. He scored 38 Test tries for his country and led South Africa for four years as captain, including a third-place finish at the 1999 Rugby World Cup.
However it was his performance at the previous World Cup, held in South Africa, that cemented his reputation in world rugby.
His play helped the Springboks get to the final on home soil, where they played the All Blacks and defeated them 15-12.
His eye for the game, his strength and fierce play under pressure was crucial - and the diminutive Van der Westhuizen's repeated tackles on New Zealand's dominant winger Jonah Lomu were among the inspirations that helped South Africa hold on for victory against the favoured All Blacks.
He retired in 2003, and was diagnosed with a form of motor neurone disease known as amytrophic lateral sclerosis in early 2011 and given a 20 per cent chance of living up to two years.
Van der Westhuizen responded to the diagnosis by forming the J9 Foundation to help those suffering from motor neurone disease, to contribute to research in Africa and raise awareness of the disease.
He was admitted to hospital in Johannesburg on Saturday, where his condition was described as "critical".
A statement on the J9 Foundation's website on Tuesday (AEDT) announced his death.
"Joost Heystek van der Westhuizen passed away at his home surrounded by his loved ones on Monday 6th February 2017," the statement said.
"Joost was best known for his incredible rugby career and in recent years has shown the same bravery and strength in his fight against motor neuron disease.
"The family remain strong under the circumstances, however are devastated at the loss.
"This is a great loss to so many around the world and the family would like to extend their greatest gratitude for the love and support shown over this difficult time."
SA rugby president Mark Alexander paid tribute to the former Springboks number nine.
"Joost will be remembered as one of the greatest Springboks - not only of his generation, but of all time," Alexander said.
"He also became an inspiration and hero to many fellow sufferers of this terrible disease as well as to those unaffected.
"We all marvelled at his bravery, his fortitude and his uncomplaining acceptance of this terrible burden."
Former team-mates and opponents spoke of their sadness at the news and their admiration for van der Westhuizen.
Joel Stransky, the man who took van der Westhuizen's pass to kick the winning drop goal in the 1995 RWC final, was one of those who posted on social media to remember the former number nine.
His contemporary, English superboot Jonny Wilkinson paid tribute, describing van der Westhuizen as "a guy I feared as an opponent, respected hugely as a player and will miss deeply as a very courageous human being."
Former Irish rugby great Brian O'Driscoll also expressed his sadness.
"RIP Joost van der Westhuizen. An incredible player and fighter to the end. The first of the new age 9s," he tweeted.