The pontiff spoke plainly, urging action on the death penalty, the migrant crisis, climate change and the plight of the poor.
Pope Francis received thunderous applause and a standing ovation from US politicians as he delivered an historic speech to the Congress.
His address ranged over several themes including migration, helping the poor, climate change and the death penalty.
Highlighting the current refugee crisis, the pontiff urged compassion.
"We the people of this continent are not fearful of foreigners because most of us ... most of us were once foreigners."
The 78 year-old Pope called on the US and the world to treat migrants and refugees in a just and humane way.
"Building a nation calls us to recognize that we must constantly relate to others, rejecting a mindset of hostility in order to adopt one of reciprocal subsidiarity, in a constant effort to do our best. I am confident that we can do this."
The Argentina-born pontiff also spoke of the plight of poor Central Americans and Mexicans who make often deadly treks across the Mexican border into the US.
"We must not be taken aback by their numbers, but rather view them as persons, seeing their faces and listening to their stories, trying to respond as best we can to their situation."
On climate change, the Pope alluded to his recent encyclical denouncing global warming as a moral challenge caused by mankind.
"Now is the time for courageous actions and strategies aimed at implementing a culture of care and at the same time protecting nature."
The Pope also called for a worldwide end to the death penalty - the US is one of the few countries that still practises it.
After his speech, the Pope was greeted by tens of thousands of cheering well-wishers.
Dozens of homeless families enjoyed a blessing from the Holy Father during their lunch as he paid a visit to Catholic Charities in the Archdiocese of Washington.
Laverne Hines Baten has described her experience meeting the pontiff.
"It was awesome! It's indescribable. I touched him, I actually stood right in front of him. He touched my hand, he touched my shoulder, he blessed the food."
Pope Francis is now in New York for more prayer services and a speech to the United Nations.
