His family said in a statement he passed away quietly surrounded by friends and relatives.
Prime Minister Justin Trudeau led the national mourning for the star with a tearful public statement.
“He loved every hidden corner, every story, every aspect of this country that he celebrated his whole life,” Mr Trudeau said, his voice breaking, on Wednesday.
“We are less as a country without Gord Downie in it. We all knew it was coming, but we hoped it was not.”
Despite his diagnosis, Downie continued to tour with Tragically Hip and produce music in the last years of his life.
The band said in a written statement: “Gord knew this day was coming – his response was to spend this time as he always had – making music, making memories and expressing deep gratitude to his family and friends for a life well lived, often sealing it with a kiss… on the lips.”
Downie collaborated with fellow Canadian and international artists. His most famous Canadian collaborations are with Richard Terfry (better known as Buck 65), Dallas Green of City and Colour and Alexisonfire, the Sadies and F#cked Up.
These collaborations do not include the musicians who helped Downie to create his solo albums.