Mercer, 15, died early Tuesday morning at the Janeway Child Health Centre in St. John's, a family friend posted on the Friends of Riley Mercer page on Facebook.
"He was the most wonderful kid you could ever meet," Rick Webber wrote on behalf of parents Bernie and Louise Mercer.
Riley was diagnosed with a rare form of brain cancer in 2011, nearly 11 years after his sister and the couple's only other child, Alex, died of the same disease.
Hundreds of people gathered around the Mercers' home on Nov. 4 for an emotional prayer vigil.
Later in November, thousands — many with no connection to the family — took part in a fundraiser at Mary Brown's restaurants to help cover the expenses of Riley's parents as they cared for him at home.
Supporters relied on power of prayer
Louise Mercer told supporters at November's vigil that she relied on her son's good humour to get through the loss of her daughter.
When her son was diagnosed with the same cancer, she said last month, Riley insisted he would recover.
"I would always tell Riley, 'You'd better not go before me,'" Louise Mercer said during an emotional tribute. "He would always laugh and say, 'I won't.' Well, Riley Mercer, I'm going to tell you one last time, you'd better not go before me."
Supporters of the Mercers had hoped that the power of prayer would help save Riley's life.
Family friends say Riley maintained his positive outlook even as the cancer ravaged his body, including the loss of sight and hearing.
"He never complains. He hasn't complained once throughout this entire ordeal," Webber told CBC News last month.