"It is almost as though a spiritual desert is beginning to spread through our world. It affects the young too, robbing them of hope and even, in all too many cases, of life itself," he said.
And he returned to the theme later in the day in an address to a gathering of 10,000 young Asian Catholics in Dangjin, when he spoke of the "idolatry of wealth, power and pleasure" and its unacceptably high human cost.
In a visit to a shrine near the western city, where the young believers were celebrating Asian Youth Day, the pope also touched on the acrimonious relationship between North and South Korea, saying both sides should not lose hope in an eventual reunification.
"Pray for our brothers in the North, that, just as in a family, there should be no winners or losers," he said, leading a moment's silence for the unity of the two countries.
"Korea is united by a common language. When in a family we speak the same tongue there is always hope," he told a young South Korean woman who expressed sorrow at the ongoing hostilities.
The mass in Daejeon, some 160 kilometres (100 miles) south of Seoul, was the pope's first public event following his arrival in Seoul on Thursday, which nuclear-armed North Korea marked by firing a series of short-range rockets into the sea.
The North, which split from the South after the 1950-53 war, rejected accusations that it had timed the launches to upstage the visit by the "so-called Pope."
Among the capacity crowd in the stadium were 38 survivors and relatives of victims of April's Sewol ferry tragedy in which 300 people died, most of them schoolchildren.
- Comfort for ferry victims -
Pope Francis offered a special prayer for the dead and their families and, before the mass, held a brief private audience with some of the relatives.
"I'm a Protestant but I believe the papal visit will help heal the wounds from the Sewol disaster," Kim Hyeong-Ki, a father of one of the victims, told AFP.
The ferry tragedy has largely been blamed on a corrupt culture of regulatory negligence that placed profit over safety.
In his homily, Francis called on South Korean Christians to combat "the spirit of unbridled competition which generates selfishness and strife" and to "reject inhuman economic models which create new forms of poverty."
He also warned of the "spirit of despair that seems to grow like a cancer" in societies where surface affluence hides deep inner sadness.
"Upon how many of our young has this despair taken its toll," he said.
Thousands without tickets for the mass had cheered and waved flags as the pope rode to the venue in an open-topped car, stopping from time to time to give a personal blessing to young children and infants held up by their parents.
"I think this is the most important and unforgettable moment of my life," said Han Hye-Jin, 26, an office worker in Daejeon.
- An evangelical call -
The pope's visit to South Korea is very much aimed at fuelling a new era of growth for the Catholic church in Asia, and his address at the youth event carried a clear evangelical message.
God, he said, "is asking you to go out on the highways and byways of this world, knocking on the doors of other people's hearts, inviting them to welcome him into their lives."
Although the Church is making some spectacular gains in Asia, Catholics still only account for 3.2 percent of the continent's population.
But expansion faces tough challenges, especially in China which prohibits its Catholics from recognising the Vatican's authority.
According to various reports, scores of Chinese Catholics were prevented from travelling to South Korea for Asian Youth Day, and Beijing also warned Chinese priests in attendance not to participate in any event involving the pope.
The centrepiece of the five-day visit to South Korea will come on Saturday, when up one million people are expected to gather in downtown Seoul for an open-air mass at which Francis will beatify 124 early Korean Catholic martyrs.