The meeting followed a surge in migrant traffic between Libya and Italy, with more than 14,000 saved from overcrowded boats in one week.
The Italian Navy said after three consecutive days of shipwrecks, hundreds may have died.
The Pope met migrant minors as well as Italian youngsters who let off dozens of white balloons inside Vatican grounds.
The children pledged to help those in need and presented Pope Francis with drawings capturing the dangers at sea.
The 79-year-old Argentine showed the children an orange life-jacket which he said had been taken from a girl who had drowned at sea.
It was given to him by a rescue worker who had wept as he described his doomed attempts to save her.
"He brought me this life-jacket and, crying, he said: 'Father, I failed. There was a girl, in the waves, but I could not save her. All that is left is her life-jacket'," Pope Francis said.
"I don't want to upset you, but you are brave and you know the truth. They are in danger: many children... they are in danger," the Pope told the children, who sat cross-legged in front of him.
"Think about this girl. What was her name? I don't know: a child without a name. Each of you must give her the name you want to. She is in heaven, she is watching over us," he added.
Children from a school in Calabria in southern Italy handed the Pope a letter in which they promised "to welcome whoever comes to our country" and "never think of those who are different from us as a dangerous enemy".
The flow of migrants and refugees into Europe via Greece and the Balkans route, which hundreds of thousands of people used in 2015, has slowed to a trickle after countries shut their borders.
But around 40,000 migrants have already landed on Italy's shores so far this year and aid organisations warn there are vulnerable groups massing in Libya and Egypt, ready to attempt the crossing at whatever cost.
"The number of minors who make the journey on their own and arrive in Europe is much higher than what we saw last year," Save the Children spokeswoman Giovanna Di Benedetto said.
"But we are increasingly coming across much younger children, children of nine or 10 years of age, who have made the journey alone or who have lost their parents or family members with whom they were travelling."