The marathon four-nation tour has already taken in Indonesia and Papua New Guinea but the 87-year-old pontiff has appeared in good spirits throughout despite fears over his health.
A formal leaving ceremony was held at the airport in capital Dili, where the pope's plane took off for the Southeast Asian city-state shortly after 12:25 pm local time (0325 GMT).
The main event of this leg was an open-air mass to what the Vatican said was an estimated 600,000 people on Tuesday in stifling tropical heat, rallying nearly half of the Catholic-majority country.
"I am so very happy, this is the first time he is here. But we are sad because he was only here for three days -- we wanted him to be here for one week," said 28-year-old banker Namaseo Xavier.
"The message that Papa Francisco gives us, that's peace for my country."
On Wednesday he spoke to young people before driving through the seaside city where thousands of people lined the streets, screaming as he drove by.
In Singapore he is set to meet the city-state's leaders, deliver a state address and hold a mass at its national stadium.
His visit was only the second papal trip to East Timor, where around 98 percent of the population is Catholic, after John Paul II in 1989.
He will stay in Singapore until Friday when he heads back to Europe after wrapping up the longest and farthest tour of his 11-year papacy.
It is home to a Chinese majority and significant Malay and Indian minorities.
Christians make up about 19 percent of the population, but majority religion is Buddhism.
