The Vatican secretary of state, Cardinal Tarcisio Bertone, delivered the papal message to the Canadian Conference of Catholic Bishops.
The Pope says he is united with the grieving families through his prayers.
He expresses his support for the victims, emergency workers and all those around them.
He is also sending a special apostolic blessing to all those affected by the tragedy.
The Prince of Wales and the Duchess of Cornwall are also extending their sympathies.
"I wanted you to know how deeply my wife and I feel for the people of the Quebecois community of Lac-Megantic who are suffering from the appalling disaster which has engulfed their town," says a letter from Prince Charles, circulated by Gov. Gen. David Johnston.
The letter also acknowledges the recent floods in Alberta, describing the recent weeks as "a most testing time for Canadians."
"However, seeing the quite extraordinary efforts which have led to the Calgary Stampede being opened on time this weekend, it is only too clear how courageous and resourceful Canadians are and we have nothing but the greatest admiration for such determination and resilience in the face of terrible adversity."
Note to readers: CORRECTS spelling Lac-Megantic