Perhaps the most interesting legend surrounding the prayer has it being composed, in part, by St. Gregory the Great. The legend has it that in the year 596, during Easter time, a pestilence was ravaging Rome. St. Gregory the Great requested a procession be held to pray that the pestilence be stopped. On the appointed day of the procession he assembled with his clergy at dawn at the church of Ara Coeli. Holding in his hand the icon of our Lady that was said to have been painted by St. Luke, he and his clergy started out in procession to St. Peter's. As he passed the Castle of Hadrian, as it was called in those days, voices were heard from above singing the Regina Caeli. The astonished Pope, enraptured with the angelic singing, replied in a loud voice: "Ora pro nobis Deum. Alleluia!" At that moment an angel appeared in a glorious light, sheathed the sword of pestilence in its scabbard, and from that day the pestilence ceased. In honor of this miraculous event, the name of the castle was then changed to Sant' Angelo and the words of the angelic hymn were inscribed upon the roof of the Church of Ara Coeli.

The traditional concluding versicle and collect, which are not part of the original antiphon, are also given below.