Pope Francis left Rome on July 24 for Canada for a chance to personally apologise to Indigenous survivors of abuse committed over a span of decades at residential schools run by the Catholic Church.
The head of the world's 1.3 billion Catholics will be met at Edmonton's international airport by Canadian Prime Minister Justin Trudeau.
The Pope's plane took off from Rome shortly after 9 a.m. local time (0700 GMT).
The 10-hour flight constitutes the longest since 2019 for the 85-year-old pope, who has been suffering from knee pain that has forced him to use a cane or wheelchair in recent outings.
The pope was in a wheelchair on July 24 and used a lifting platform to board the plane, an AFP correspondent accompanying him said.
Pope Francis' Canada visit - which he has called a "penitential pilgrimage" of "healing and reconciliation" - is primarily to apologise to survivors for the Church's role in the scandal that a national truth and reconciliation commission has called "cultural genocide".
From the late 1800s to the 1990s, Canada's government sent about 150,000 First Nations, Metis and Inuit children into 139 residential schools run by the Church, where they were cut off from their families, language and culture. Many were physically and sexually abused by headmasters and teachers.
Thousands of children are believed to have died of disease, malnutrition or neglect.
Since May 2021, more than 1,300 unmarked graves have been discovered at the sites of the former schools.
A delegation of Indigenous peoples travelled to the Vatican in April and met the pope - a precursor to Pope Francis' six-day trip - after which he formally apologised.
In the community of Maskwacis, some 100 kilometres (62 miles) south of Edmonton, the pope will address an estimated crowd of 15,000 expected to include former students from across the country.
"I would like a lot of people to come," said Charlotte Roan, 44, interviewed by AFP in June. The member of the Ermineskin Cree Nation said she wanted people to come "to hear that it wasn't made up".
Others see the pope's visit as too little too late, including Linda McGilvery with the Saddle Lake Cree Nation near Saint Paul, about 200 kilometres east of Edmonton.
"I wouldn't go out of my way to see him," said the 68-year-old.
"For me it's kind of too late, because a lot of the people suffered, and the priests and the nuns have now passed on."
Ms. McGilvery spent eight years of her childhood in one of the schools, from age six to 13.
"Being in the residential school I lost a lot of my culture, my ancestry. That's many years of loss," she told AFP.
After a mass before tens of thousands of faithful in Edmonton on July 26, the pope will head northwest to an important pilgrimage site, the Lac Sainte Anne.
Following a visit to Quebec City from July 27-29, he will end his trip in Iqaluit, home to the largest Inuit population in Canada, where he will meet with former residential school students, before returning to Italy.
Pope Francis is the second pope to visit Canada, after John Paul II, who visited three times (1984, 1987 and 2002).
Some 44% of Canada's population is Catholic.