Their nearly hour-long first meeting came as Mr Obama's administration remains deeply split with the church over abortion and contraception.
Mr Obama arrived at the Vatican amid the pomp and tradition of the Catholic Church, making his way to greet the Pope after a long, slow procession through the hallways of the Apostolic Palace, being led by colourful Swiss Guards and accompanied by ceremonial attendants.
The president bowed as he shook hands with the pontiff before the two sat down at a wooden table in the Papal Library.
"It is a great honour. I'm a great admirer," Mr Obama said. "Thank you so much for receiving me."
The two were scheduled to meet for just half an hour, but their private discussion lasted 52 minutes.
Mr Obama seemed buoyed by the meeting as the emerged, and Pope Frances greeted a handful of Mr Obama's senior advisers.
Mr Obama's secretary of state John Kerry, a Catholic, pronounced himself "a great admirer of everything you've been doing, as a Catholic, for the church".
The President and Francis then exchanged gifts, with the Pope handing the president a plaque and an encyclical, or papal letter.
Mr Obama presented the Pope with a seed chest with fruit and vegetable seeds used in the White House Garden, mentioning he had heard the Pope was opening the gardens at the papal summer residence to the public.