He made the remarks during a visit to the Armenian capital, Yerevan, for commemorations of the massacre.
Armenia and many historians say up to 1.5 million Armenian Christians were killed by Ottoman forces in 1915.
Turkey has always disputed that figure and rejects using the term "genocide".
It says the deaths were part of a civil conflict triggered by WW1.
The row over how to characterise the killings has continued to sour relations between Armenia and Turkey, as well as drawing in other countries such as Germany, whose parliament recently declared the killings to be genocide.
- Q&A: Armenian genocide dispute
In an address to Armenia's President Serzh Sargsyan and the diplomatic corps, the Pope appeared to have added the word "genocide" to his prepared text.
"This tragedy, this genocide, has unfortunately marked the start of a sad series of great catastrophes of the last century," he said.
He added that the killings were "made possible by twisted racial, ideological or religious aims that darkened the minds of the tormentors even to the point of planning the annihilation of entire peoples."
The remarks were met by a standing ovation.
"One cannot but believe in the triumph of justice when in 100 years... the message of justice is being conveyed to mankind from the heart of the Catholic world," President Sargsyan said.
There was no immediate reaction from Turkey, which last year recalled its envoy to the Vatican after the Pope referred to "genocide".
The envoy was kept away for 10 months.