The Pope said the gangsters were effectively "excommunicated", or banished, in the eyes of the Church.
Earlier, the Pope visited the jailed father of a three-year-old boy who had been killed in an apparent mob hit over an unpaid drug debt.
The Pope has repeatedly spoken out against organised crime and corruption.
His latest condemnation, delivered before a crowd of tens of thousands, described the 'Ndrangheta as the "adoration of evil and contempt of the common good".
"Those who in their lives follow this path of evil, as mafiosi do, are not in communion with God," the Reuters news agency quoted him as saying. "They are excommunicated."Meeting with prisoners
The 'Ndrangheta is a network of clans in the "toe" of Italy that dominates the country's cocaine trade.
It is one of the most powerful mafia organisations in Italy, along with the Sicilian Cosa Nostra and the Neapolitan Camorra.
Earlier on Saturday, the Pope visited a prison to meet the jailed relatives of "Coco" Campolongo, a three-year-old boy who was killed along with his grandfather in an execution-style shooting in Calabria.
"It must never again happen that a child suffers in this way," the Pope said.
The Pope also met hundreds of other inmates at Castrovillari prison, many of whom are serving time for mafia-related crimes.
The AFP news agency reports that many of the prisoners wept as the Pope greeted them.