Up to 1.5 million people are expected for the pope's weekend visit, which caps the World Meeting of Families, an international gathering of Catholics.
Impressive security measures were in place in the so-called "city of brotherly love", with cars barred from the downtown area which was turned into a pedestrian-only zone.
In the early morning hours, the still empty streets were divided by metal barricades along the pope's route. On some roads, large concrete traffic barriers barred the way.
The pontiff will make the short flight from New York in the morning, touching down in Philadelphia at 9:30 am (1330 GMT) before heading straight to mass at the Cathedral Basilica of Saints Peter and Paul.
In the afternoon, he is due to address immigrants at the city's historic Independence Hall before greeting huge crowds at the Festival of Families, an event that takes place every three years.
On Sunday, he will meet with American bishops, visit a prison and lead a farewell mass on the Benjamin Franklin Parkway before flying out of the country in the evening.
His reform-minded approach to social issues, humility and focus on the most vulnerable has struck a chord across the racial and socioeconomic divide in a country increasingly questioning its place in the world.
New York treated the pontiff to a rock-star reception, shutting down the city with draconian security measures to allow him ease of movement.
A sea of 80,000 people screamed out in joy as he proceeded through Central Park in his popemobile before celebrating mass at Madison Square Garden.
Once again, the 78-year-old Argentine focused on society's poorest, in a message voiced time and again in America's financial capital, a city of staggering wealth but also deprivation.
