81-year-old Pope Francis listened alongside 20,000 Roman Catholic faithful as the meditations re-enacting Christ's crucifixion were read in the torch-lit Colosseum.
The pontiff delivered a message of his own at the end of the service regarding shame and repentance.
He described a modern world where pride, arrogance and selfishness often trumped humility and generosity, and urged people - including ministers of his church - to rediscover the capacity to feel shame for their roles in the world's ills.
Since his election in 2013, Pope Francis has often encouraged priests and prelates to live simply and serve others rather than seeking careers and status in the church or in society in general.
The Way of the Cross service marks 14 events called stations, leading to Jesus' burial.
This year, each was written by high school and college students in Rome.
Good Friday, the most sombre day of the Christian liturgical calendar, commemorates the day the Bible said Jesus was crucified.
The pope will lead an Easter vigil service Saturday night and will deliver his twice-yearly 'to the city and the world' message on Easter Sunday.
Rome on high alert for Easter after anti-terrorism raids and arrests in Italy
Earlier this week, police in Italy conducted raids and arrested seven people with suspected Islamic State (IS) links, including one man who was allegedly planning a truck attack.
The Colosseum, in Rome's historic centre, is one of several tourist attractions where police have set up military jeeps and armoured vehicles to form barriers against potential vehicle attacks.
Police checked more participants as they approached the area of the Way of the Cross procession than they did last year.
Several cordons have also been established near the Vatican.