Italian Paolo Nespoli, 60, admitted that despite the bird's eye view of Earth he too remained "perplexed", while American Mark Vande Hei said seeing the planet from space made them "realise how fragile we are".
The Argentine pontiff sat at a Vatican desk, facing a wide-screen television on which the astronauts from America, Russia and Italy could be seen floating together in their blue suits.
"Good afternoon... or good evening. I imagine time passes differently at the space station, right?" the pope quipped.
"Astronomy makes us think about the universe's boundless horizons, and prompts questions such as 'where do we come from, where are we going?'" he mused.
A 30-second delay in the satellite feed gave Nespoli, Vande Hei, Americans Randolph (Randy) Bresnik and Joseph Acaba, and Russians Sergej Nikolaevic Rjazanskij and Alexandr Misirkin time to weigh up life's biggest questions.
"Our aim here is to spread knowledge, (but) the more we learn, the more we realise we do not know," admitted Nespoli, who is on his third trip into space.
"I would like people like you, theologians, philosophers, poets, writers, to come to space to explore what it means to be a human in space," he said, as Francis nodded and smiled.
US mission commander Bresnik told the Argentine that from the visible thinness of the planet's atmosphere shows how fragile life is on earth.
'Future of humanity'
But the pope had not finished: what, he wanted to know, was their opinion of love as a force that moves the universe? What was their source of joy up in the space station, and how did a life without gravity change their view of the world?
The crew took it in turns to get their philosophical caps on, and not even a technical hitch which temporarily interrupted the interview, or the lack of a Russian translator, could throw the space travellers off course.
"I get the most joy by looking outside every day and seeing God's creation, maybe a little bit from his perspective," Bresnick said.
Far from wars, famines, pollution or human folly, he said "the future of humanity looks better from up here".
Bresnik, 50, a former Marine Corps aviator who goes by the nickname "Komrade", made his fifth career excursion outside the space station this month to carry out crucial repairs to the ISS's robotic arm with NASA colleague Acaba.
Acaba, 50, the first person of Puerto Rican heritage to become an astronaut, cheerfully said hello to the pope in Spanish before tackling the question on how the men deal with 'up' and 'down' losing their meaning in space.
Francis is not the only Roman Catholic leader to have put in a call to the star-covered heavens.
The first pope to get on the line to space was Benedict XVI in 2011, who rang the ISS -- which has been continuously occupied since 2000 -- when Nespoli was once again among the crew.
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