Hailed as one of South Africa's greatest, Van der Westhuizen played 89 tests between 1993 and 2003 and scored 38 test tries for the Springboks, a record at the time. He captained the team to the bronze medal at the 1999 World Cup.
"Joost will be remembered as one of the greatest Springboks - not only of his generation, but of all time," SA Rugby President Mark Alexander said in a statement calling him "one of the best scrumhalves world rugby has ever seen".
"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."
Van der Westhuizen was given two-and-a-half years to live when he was diagnosed with amyotrophic lateral sclerosis, a form of motor neurone disease, in 2011.
He put his energy into the J9 Foundation, which seeks to help other suffers cope with the disease.
"It is with great sadness that we confirm the passing of Joost," the foundation said. "He passed away in his home surrounded by his loved ones."
Francois Pienaar, the Springbok captain during the 1995 World Cup, told TimesLive: "Joost was extraordinary on the field and fought until the end. We will miss him deeply."
Former Bok coach Heyneke Meyer, who taught Van der Westhuizen as a schoolboy and later coached him in provincial rugby, spoke of his bravery and fighting spirit.
"At the 1999 World Cup he played with a knee ligament damage. As a player and person he was a warrior and a fighter."
South African President Jacob Zuma said: "South Africa has lost a legend and one of the best rugby players that the country has ever produced."
Ireland great Brian O'Driscoll tweeted his admiration for how the dynamic Van der Westhuizen had changed scrumhalf play.
"RIP Joost van der Westhuizen. An incredible player and fighter to the end. The first of the new age 9's."
New Zealand flyhalf Dan Carter said: "He was one of the few non All Black players I adored. Such sad news! #RIPJoost."
(Editing by Robin Pomeroy)
