Real name, David Evans, the guitarist gave a special performance to raise awareness about cancer.
#TheEdge meeting #PopeFrancis in Vatican today pic.twitter.com/01a3O0cUhk
— Andreas Stetten (@AStetten) April 29, 2016
He was in Rome as part of a special Vatican conference on regenerative medicine called Cellular Horizons.
The Edge performed four songs for around 200 doctors, researchers and philanthropists.
He sang and played guitar alongside a choir of seven Irish teenagers.
He played acoustic guitar and sang a cover of Leonard Cohen's "If it be your will", and versions of U2 songs "Yahweh", "Ordinary love" as well as "Walk on".
The Edge dedicated "Walk on", written in 2000 for Myanmar democracy advocate Aung San Suu Kyi when she was under house arrest, to Pope Francis.
He described him as "the people's pope,", saying: "he's doing an amazing job and long may he continue."
Mr Evans described the Sistine Chapel as "the most beautiful parish hall in the world," according to Reuters.
The ceiling of the Sistine Chapel was painted by Renaissance artist Michelangelo between 1508 and 1512.
#TheEdge in the History!! #SistineChapel April30,2016
— dani mattei (@daniDpVox) May 1, 2016
via @holliebe & @U2NT_ (on fb)#U2 #U2ieTourItaliaNews #U240 pic.twitter.com/moBTG0CMCo
The Edge's father died from cancer in March and his daughter overcame leukemia
He sits on the board of foundations working for cancer prevention.
David Evans joked about his band mate, U2 frontman, Bono on stage: "When they asked me if I wanted to become the first contemporary artist to play in the Sistine Chapel, I didn't know what to say because usually there's this other guy who sings."
He went on: "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 said.
He thanked Pope Francis and other Vatican officials "for allowing us to use the most beautiful parish hall in the world".
The Vatican meeting was addressed by US Vice President Joe Biden as well.
"The most beautiful parish hall in the world" - In epic event, @U2's #TheEdge rocks the Sistine at cancer summit. pic.twitter.com/3pQftURmYS
— Rich Raho (@RichRaho) May 1, 2016
