Francis welcomed the prime ministers and presidents of 27 EU member countries to the Vatican as part of commemorations marking the bloc's 60th birthday.
Speaking in a lavishly frescoed room, he said: "Invoking upon Europe the Lord's blessings, I ask him to protect her and grant her peace and progress."
The address came with a call to pursue greater international solidarity in the face of "modern forms of populism" which restricts people to "narrow vision".
Appearing to reference a rise in anti-immigrant and nationalist sentiment across the continent, Pope Francis continued: "Europe finds new hope when she refuses to yield to fear or close herself off in false forms of security."
The gathering of leaders in Rome at the weekend marks 60 years since the 1957 Treaty of Rome which established what was then called the European Economic Community.
From six nations - Belgium, France, Italy, Luxembourg, the Netherlands and West Germany - the bloc has grown to include 28 states.
With Theresa May expected to trigger Article 50 - the legislation which sets out the UK's withdrawal from the EU - next week, Britain was not represented at the Papal event.
Pope Francis called for a return to the values of the founders of the European in the face of current crises, the common denominator of which was "the spirit of service".
He said: "There is the economic crisis that has marked the past decade; there is the crisis of the family and of established social models; there is a widespread "crisis of institutions" and the migration crisis.
"Returning to the thinking of the founding Fathers would be fruitless unless it could help to point out a path and provide an incentive for facing the future and a source of hope.
"When a body loses its sense of direction and is no longer able to look ahead, it experiences a regression and, in the long run, risks dying."