The Argentine-born pontiff walked up to his podium flanked by five prison inmates from the hard-hit northern Italian city of Padua and five Vatican doctors and nurses.
Their presence was a tribute to the victims of a disease that has officially claimed nearly 19,000 lives in surrounding Italy — a higher toll than in any other country and nearly a fifth of the world's reported total.
The dramatic Way of the Cross ceremony around Rome's sumptuously illuminated Colosseum has taken place every year since 1964, normally with thousands of faithful.
But both the Vatican and Italy have been under a virus-imposed lockdown and the 83-year-old pontiff has been communicating with the world's 1.3 billion Catholics by live-stream.
Earlier, Francis had said that medics and priests who died after becoming infected while looking after COVID-19 victims “gave their lives out of love, like soldiers at the front”.
Dozens of priests and at least 100 doctors are believed to have died of the novel coronavirus in Italy.