The visit, which is the pope's sixth trip since the beginning of his pontificate, has attracted considerable media interest since it was announced in September.
Around 80 media representatives are travelling with the pope, including correspondents from news agencies, newspapers, radio and television broadcasters and online outlets, as well as camera operators, photographers and TV producers.
Journalists from all three countries on the itinerary are also on board.
The visit includes a return to Peru, where Robert Prevost, before becoming pope, served as a priest and later as a bishop and ordinary of a diocese for a combined period of more than 20 years.
It also takes him to Argentina, which his predecessor, Pope Francis, never visited.
Questions had arisen over whether the trip would go ahead after the pope underwent surgery to remove a lung tumour on October 13.
The intensive programme includes 14 flights and a visit to an area of the Peruvian Andes more than 3,000 metres above sea level.
Before leaving Rome's Gemelli Hospital on October 17, the Vatican said preparations for the trip were continuing.
The list of media representatives allowed on board the papal plane was published while the pope was still in hospital, providing the first confirmation that he was determined to travel.
Prof. Stefano Margaritora, who led the surgical team that removed the tumour, said the pope had put all his effort into recovering and that there were no medical reasons preventing him from travelling.
The Vatican later said no further oncological treatment was necessary.
On October 26, the Vatican Press Office confirmed that medical examinations had shown the pope was in good condition to travel.
Doctors said he had followed their recommendations carefully, and the Vatican said the trip would go ahead according to the previously announced programme.
The Vatican said the pope was looking forward to the visit with great joy and enthusiasm.
It said the trip was intended to strengthen ties with local churches, support the faithful in their mission and bring a message of faith, hope and peace to the people of Uruguay, Argentina and Peru.
The media representatives will fly with the pope on 14 flights aboard aircraft operated by different airlines.
They are expected to meet him several times on board, including shortly after departure from Rome, during longer flights between countries and at a press conference at the end of the trip.
The pope does not have his own aircraft. He travels from Rome on planes operated by Italian airline ITA and usually uses local carriers while abroad.
The flights from Rome to Montevideo on Friday and from Lima back to Rome on November 16-17 are each expected to take around 14 hours.
Bob Dylan meets Leo at Vatican
On Wednesday, Leo met singer-songwriter and Nobel Prize in Literature laureate Bob Dylan in a private audience at the Vatican.
Leo had previously quoted Dylan's 1963 song Go Away You Bomb, which opposes nuclear weapons, in the introduction to a book on peace published by the Vatican publishing house LEV.
Dylan was due to perform in Rome on Thursday as part of his concert tour.
In 1997, Dylan performed in Bologna during the National Eucharistic Congress in front of Pope John Paul II and 300,000 young people.
(sp/gs)
Source: PAP