"Almighty and eternal God, provident refuge of the suffering, look with compassion on the affliction of your children who suffer from this pandemic," Francis said.
It is the second consecutive Easter taking place under COVID-19 restrictions, with the Vatican following Italian guidelines.
Italy has seen a resurgence in coronavirus infections and deaths over the last month and the government has tightened restrictions on businesses and movements to contain the virus.
On Friday night, the pope is leading a Via Crucis (Way of the Cross) procession on the basilica's outdoor steps in an empty St. Peter's Square.
It will be the second time the procession is not being held at Rome's Colosseum since the modern-day tradition was re-introduced by Pope Paul VI in 1964.