Tens of thousands of pilgrims joined him for the Way of the Cross ceremony, recalling Jesus' crucifixion.
Among the cross bearers were Syrian and Iraqi refugees, and Nigerians who had escaped Boko Haram persecution.
The service came a day after almost 150 people were killed in an al-Shabab attack on a Kenyan university.
"We still see today our persecuted brothers, decapitated and crucified for their faith in you [Jesus], before our eyes and often with our complicit silence," Pope Francis said, presiding over the ceremony at the Colosseum.
Earlier, he condemned the attack in Kenya, where Christians were singled out and shot, as an act of "senseless brutality".
In another Good Friday ceremony, Pope Francis listened as the Vatican's official preacher Raniero Cantalamessa denounced the "disturbing indifference of world institutions in the face of all this killing of Christians".
He too mentioned the Kenya attack, as well as the beheading of 22 Egyptian Coptic Christians by Islamic State (IS) militants in Libya in February.
Pope Francis has spoken out against the persecution of Christians before, saying that the world would be justified using military force to combat the "unjust aggression" by IS.
Pope Francis has condemned the "complicit silence" about the killing of Christians during a Good Friday service in Rome.