Francis was seen off by Italian Prime Minister Enrico Letta as he departed from Rome's Fiumicino airport shortly before 9.00am. In keeping with his trademark simplicity, the pope carried his own hand luggage onto the plane.
The 76-year-old Pope has a busy schedule for the week-long trip, starting with a meeting with Brazilian President Dilma Rousseff.
During his time in Rio de Janeiro, the Argentine Pope will enjoy a couple of helicopter rides and two trips to the famous Copacabana beach to work with young people.
Pope Francis will also visit the city’s Manguinhos favela and have lunch with Brazilian cardinals and other Catholic Church leaders in the country.
He is the first pope from Latin America, although the pontiff is of Italian descent.
The Brazil trip comes just two weeks after Pope Francis made his first trip outside of Rome, when he visited Lampedusa. His visit to the Italian island - the landing spot for thousands of boat migrants every year - was hailed by rights groups and criticized by anti-immigrant politicians.
Pope Francis departs from Rome just days after a Latin American scandal erupted in the Vatican. On Friday Italian weekly L’Espresso alleged that prelate Battista Ricca had gay relations when working at the Vatican embassy in Montevideo, the Uruguayan capital.
Although a predominantly Catholic country, Uruguay is one of the most liberal of the Latin American nations. In April, the government voted to legalize gay marriage, just months after the country legalized abortion.