"Increasingly inhumane - and even politically celebrated - measures are being taken to treat these 'undesirables' as if they were rubbish and not human beings," the Pope said on Thursday.
States that mistreated migrants or disregarded their rights were committing "grave crimes", Leo XIV continued.
At a meeting with representatives of social movements in the Vatican, the head of the Church criticised growing inequality, the abuse of migrants and the exploitation of poor countries.
Peoples were being robbed and forced into poverty, while a small minority was becoming immeasurably rich.
The Pope warned of a "globalisation of powerlessness" that must be overcome by a "culture of reconciliation and commitment".
He spoke of an approach that creates and increases inequalities and criticised an increasing "idolatry of profit" and dependence on new technologies that enable progress but at the same time increase inequality and unemployment.
"A poor church for the poor"
Leo XIV also criticised the exploitation of natural resources in poor countries. The mining of coltan and lithium is often associated with child labour, violence and political destabilisation.
He also condemned the spread of synthetic drugs such as fentanyl, which was "not only a crime of drug traffickers", but an expression of a "profit-orientated system without global ethics".
Despite his urgent warnings, the Pope called for hope and commitment. "Earth, home and labour are sacred rights - and it is worth fighting for them," said Leo XIV.
He described the social movements as "poets of solidarity" and demanded: "The Church must be with you: a poor Church for the poor, a Church that bends, a Church that takes risks, a courageous, prophetic and joyful Church!"
Representatives of the Münster Institute for Theology and Politics took part from Germany. "Pope Leo has taken a very clear position on the crisis-ridden present," they said.
The Pope's clear words are an appeal to the Church to stand alongside initiatives that support refugees and oppose their rejection or inhumane deportation.
"In Germany, one starting point for this would be church asylum, which should receive far more support from church leaders and parishes in order to open up protective spaces against deportations."