The 78-year-old Jesuit pontiff, the first pope from his "beloved South America," has said he wants to highlight the plight of the poor on his home continent.
He is due to land in Ecuador's capital Quito at 3:00 pm (0730 IST) and will give a Holy Mass in eight languages early tomorrow.
Francis's last visit to South America was a triumphant trip to Brazil that culminated with some three million people gathering in Rio de Janeiro along Copacabana beach for a mass at the end of a Catholic youth festival.
But the region has seen declining numbers as more people turn to Protestant churches.
"I want to bear witness to the joy of the Gospel and bring God's tenderness and care," the pope said before leaving for South America.
"Especially children in need, the elderly, the sick, the imprisoned, the poor, those who are victims of this throwaway culture."
The papal visit coincides with a time of political tension in Ecuador.
Embattled President Rafael Correa, an avowed admirer of Francis who describes himself as a "humanist Catholic of the left," has faced weeks of protests demanding his ouster over his policies, including an initiative to increase inheritance taxes.
"How the Church is changing! What a strong message you are bringing."
Correa will meet with the pope late tomorrow.
Since he was elected pope in March 2013, Francis has become an outspoken advocate for the poor and on social and environment issues.
Last month, he urged the world to act quickly to prevent "extraordinary" climate change from destroying the planet.
In his ninth trip abroad, the three countries the pope is visiting are predominantly Catholic and have long struggled with poverty and inequality, which especially afflict the indigenous population.
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