Catalonia's La Vanguardia newspaper asked the Pope if he was worried about the "conflict" between Spain and Catalonia.
The pontiff replied that he was worried about "any division" and expounded on what he felt were the differences between "independence for emancipation and independence for secession."
While admitting that "there are countries with cultures so diverse that not even glue could stick them together", such as the "very clear case" of Yugoslavia, he asked himself "if it is so clear in other cases, in other countries, which have until now been together."
He said, "They must be studied on a case-by-case basis: Scotland, Padania [an area in northern Italy], Catalonia. There will be just cases, and cases that are not just, but the secession of a nation without a history of forced unity must be handled with care, and analyzed case-by-case."
Pope Francis also said that he was "very worried about the youth unemployment rate, which in some countries is over 50%".
He added: "Someone told me that 75 million young people under the age of 25 in Europe are on the dole. It's an outrage. But we're throwing away a whole generation to maintain an economic system that can't last, a system that needs to create wars to survive as grand empires have always done.
"But as we can't have a third world war, they now create regional wars."
The pope went on to give his thoughts on subjects including inter-faith relations, the rise of atheism, and the future of the Catholic church.
But despite being asked, the Argentinean Bishop of Rome refused to say who he would be supporting in the football World Cup.
"The Brazilians asked me to be neutral!" he said. "And I keep my word because Brazil and Argentina are always opposed to each other."