The 78-year-old head of the Catholic Church will lead a giant, open-air mass, which up to 1.5 million people are expected to attend in downtown Philadelphia at the end of the World Meeting of Families.
Earlier in the day, he is due to meet bishops and visit a prison to talk to around 100 inmates.
Neither has a meeting with victims of pedophile priests been ruled out. Philadelphia is one of the cities where the scandal was most serious in the 1980s.
If the meeting fails to materialize, victims of the sex abuse scandal will be very disappointed.
The pope's predecessor, Benedict XVI, met victims of sex abuse scandal in Boston in 2008.
The 10th overseas tour of the pope began in Cuba, where he urged the country to continue down the path of reconciliation.
Fresh from helping broker dialogue between Havana and Washington, which led to the resumption of diplomatic ties, Francis was welcomed personally by President Barack Obama at the airport and then at the White House.
At every step of the way -- in Cuba, as in Washington, New York and Philadelphia, he has been greeted by cheering crowds of Catholic faithful and those drawn to his message and his humility.
In America in particular, a country famous for its large cars, there was delight that he chose to be driven around in a modest Fiat 500 or his open-sided popemobile to meet, embrace, listen and speak with people.
But it was during meetings with the disadvantaged -- a homeless lunch or meeting immigrant school children -- that Francis appeared most at ease.
He has been constant and firm on immigration, the topic that divides Americans in the nascent 2016 election campaign.
From the moment the pope arrived in Washington, he presented himself as the son of immigrants -- Italians to Argentina.
- Immigrants -
He has repeatedly reminded Americans of their immigrant roots and urged them to welcome others to share in the American dream.
Through references to Abraham Lincoln and Martin Luther King, the pope called on Americans to follow their example and go back to the nation's founding values.
In a historic address to Congress, he called on politicians to take responsibility for crafting a fairer economic system, confront global warming, restrict the arms trade and abolish the death penalty.
All these positions are at odds with the conservative wing of the Republican Party but criticism of his speech has been moderate.
He also defended the traditional family and called on societies to allow young couples to start a family and have children.
"Families quarrel and sometimes plates can fly and children bring headaches, and I won't speak about mothers-in-law," he said in an off-script speech laden with jokes lapped up by families in Philadelphia.
"But those difficulties are overcome with love," he said in words of wisdom woven with a common touch, in the style that has endeared him to an audience beyond the world's 1.2 billion Catholics.
Another poignant moment was his visit to the 9/11 Memorial in New York, the site of the September 11, 2001 attacks, where he condemned violence in the name of religion and preached inter-faith tolerance.
Throughout the packed schedule, the pope has looked happy and relaxed, but at times showed signs of fatigue due to a hip problem.