Arriving on the island, where he met asylum seekers due to be deported to Turkey under the controversial EU agreement, he said the visit was "marked by sadness".
The Pope visited the Moria detention camp where 2,300 people are being held by the Greek authorities, and where he will have lunch with eight refugees.
Some of the migrants wept as they met the Pontiff. He was shown artwork by some of the children detained there and was given a picture by one girl, telling his staff: "Don't fold it I want it on my desk."
Those who had not been chosen to meet the Pope held banners reading "We are also human" and "Pope you are our hope".
Pope Francis was greeted by the Greek Prime Minister Alexis Tsipras who said the visit was "historic and important".
He said he was proud of his country's response to the migrant crisis when other countries in Europe were "erecting walls and fences to prevent defenceless people from seeking a better life".
Macedonia, Croatia and Hungary erected 10ft razor-wire topped fences to keep stop refugees from crossing.
He will also visit the sea to pay respects to the hundreds who have died trying to make the crossing after fleeing war-torn countries in the Middle East and north Africa.
It was from the coast of Lesbos that images of the body of three-year-old Aylan Kurdi being carried from the sea where he had drowned shocked the world in September.
Speaking on the plane ahead of his trip, Pope Francis said: "This is a trip that is a bit different than the others ... this is a trip marked by sadness.
"We are going to encounter the greatest humanitarian catastrophe since World War Two. We will see many people who are suffering, who don't know where to go, who had to flee.
"We are also going to a cemetery, the sea. So many people died there ... this is what is in my heart as I make this trip."
According to Greek TV, the Pope has agree to take 10 refugees back to Italy with him - eight Syrians and two Afghans - in what would be seen as a hugely symbolic gesture.
However, the Vatican has refused to comment on the report.
Italy has it own migrant crisis to deal with on the island of Lampedusa, which also sees hundreds trying to cross each year, and the country has repeatedly asked the EU for help.
Pope Francis visited refugees there in 2013 where he spoke of the "global indifference" to the plight of refugees.
More than a million migrants entered the EU last year, about half landing on the beaches of Lesbos.
Greece, still suffering from the recession, had continuously appealed to the EU for help after borders were closed to migrants trying to cross putting more pressure on the impoverished country.
But the EU agreement to send refugees back to Turkey to try to stem the flow has been controversial and the Pope's visit, although humanitarian, will shine a spotlight on the human cost of that deal.
Relief agencies have criticised conditions in the camp as "unacceptable", with "unaccompanied minors locked up behind barbed wire".
Gauri van Gulik, deputy Europe director at Amnesty International, said: "The Pope's visit comes at a pivotal moment: right as Europe is gearing up to send thousands of refugees back to Turkey, locking them up in the meantime in horrible conditions.
"These are people who fled the horrors of Islamic State, the Taliban, bombings in Syria and more. They deserve Europe's protection and care, and hopefully the Pope can shed light on their plight."
There was a small protest outside the Moria detention camp on Friday, with demonstrators saying the Pope should do more.
Overnight graffiti saying "Papa don't preach" had to be removed after it was sprayed at the venues where Pope Francis is due to speak.
Hospital doctor Stathis Pavlou, said: "We should be helping these people, not locking them up."
The head of the Catholic Church in England and Wales, Cardinal Vincent Nichols, has criticised David Cameron's resettlement programme for Syrian refugees, saying it was a "great disappointment".
He told the Radio 4 Today programme that British help for refugees was too slow and "we could be doing more".
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