Edwards, who was 49, died at home, tour officials said.
The veteran caddie was the inspiration for a national campaign to raise money to fight the disease, formally known as amyotrophic lateral sclerosis, or ALS.
"Damn this disease, damn it," Watson said after his round in the Masters at Augusta, Ga. "We're going to find a cure. We don't have one right now."
Edwards was diagnosed with ALS, which attacks nerve cells in the brain and spinal cord, in January 2003, but continued to caddie for Watson throughout the year. He was unable to return in 2004.
"Bruce put up a brave fight in his battle with this terrible disease and, with Tom's assistance and support, brought extensive attention to ALS and the fight to find a cure," said Tim Finchem, PGA Tour commissioner.
Edwards began working for Watson in 1973. He once called Watson "the older brother I never had."
Edwards, a native of Hartford, Conn., lived in Ponte Vedra Beach with his wife and two stepchildren.