The 72-year-old comedian and actor started out as a folk singer before developing the stand-up act that made him famous and led to a career in television and film.
He was often pictured with his banjo but has now said he can no longer play it as he prepares to travel across the United States by rail for a new ITV series.
Connolly said Parkinson’s Disease has particularly affected his left hand, preventing him from playing his favourite instruments.
In an interview in Canada to promote his stand-up tour, he said: “I’m starting a documentary series in a month’s time following the railways around America.
“I’m going to festivals and state fairs and all that.
“I’ve been longing to do it for a long time. The only trouble is that we’re going to bluegrass festivals and I’ve got Parkinson’s Disease and it’s really affected my left hand and I can’t play the banjo or guitar any more, but I’ll join in on the singing at least.
“It’s been a rough go between that and the cancer. I kept telling my wife that haemorrhoids couldn’t be far behind.”
Connolly disclosed in 2013 that he had been diagnosed with Parkinson’s and prostate cancer on the same day.
He has since been given the all-clear from cancer and will travel through 28 states and 8,000 miles by train later this year in new ITV documentary series Billy Connolly’s Tracks Across America.
His wife, Pamela Stephenson, said in an interview last year that she had noticed her husband’s hand shaking for many years, but assumed it was because he had spent too long playing the banjo rather than a sign of Parkinson’s.
She said: “I’ve actually noticed his hand shaking for many, many years. I used to think he was playing the banjo a bit too much. I think it’s been there for a long time.”