"If someone is gay and he searches for the Lord and has good will, who am I to judge?" the pope asked.
The comments were made during an 82-minute exchange with reporters aboard his plane as he was returning from his first international trip as leader of the Catholic Church.
"We shouldn't marginalize people for this. They must be integrated into society," Francis said.
While the comments did not signal any change in church policy, the pope's words do mark a sharp shift in tone. The Catholic Church has long described homosexuality as "intrinsically disordered," and Francis' immediate predecessor, Pope Benedict XVI, signed a document in 2005 saying homosexual men should not be priests.
"The holy father made a really good step in the right direction," Deacon Morgan with the Church of the Blessed Sacrament in Hollywood said in a statement. "Basically, nothing has changed. The church rule is no sex outside of marriage. But he has made a very positive step towards reconciliation and healing."
The largest U.S. gay rights group, Human Rights Campaign, used the word "hopeful" in describing the pope's comments. But HRC President Chad Griffin said, "As long as millions of LGBT Catholic individuals, couples and youth alike are told in churches big and small that their lives and their families are disordered and sinful because of how they are born - how God made them - then the church is sending a deeply harmful message."
Francis also said he wanted a greater role for women in the church, but he insisted that "the door is closed" to ordaining them as priests.
Funny and candid, Francis' exchange with the media was exceptional. While his predecessor responded to only a few pre-selected questions during his papal trips, Francis did not dodge a single query, even thanking the journalist who asked about reports of a "gay lobby" inside the Vatican and allegations that one of his trusted monsignors was involved in a gay tryst.
Francis said he investigated the allegations against the clergyman according to canon law and found nothing to back them up. He took journalists to task for reporting on the matter, saying it concerned issues of sin, not crimes like sexually abusing children. And when someone sins and confesses, he said, God not only forgives - he forgets.
The Associated Press contributed to this report.