The 54-year-old guitarist, whose real name is David Evans, was in Rome over the weekend to attend a Vatican conference on regenerative medicine called 'Cellular Horizons', Ansa reported.
On Saturday night, he took time out from discussing medicine to perform a mini-concert for a crowd of 200 researchers, scientists and philanthropists who were also attending the event.
Backed by a choir of seven teenagers from Ireland, Evans delivered a short acoustic set, belting out the Leonard Cohen hit “If it be your will” before performing the U2 classics “Yahweh”, “Ordinary love” and “Walk on.”
During his set, Evans thanked Vatican officials for giving him the chance to perform at the chapel which he described as "the most beautiful parish hall in the world".
The chapel is world famous for its 16th century frescoes by Renaissance master Michelangelo.
"Being Irish you learn very early that if you want to be asked to come back it's very important to thank the local parish priest for the loan of the hall," he joked.
Evans then dedicated his final song, “Walk on”, to Pope Francis, who he briefly met on Friday. He described the Pontiff as “the people's pope.”
The guitarist, who lost his father to cancer in April and whose daughter Sian successfully overcome leukaemia in 2010, sits on the board of several foundations working to cure cancer.