Gregory was born around 540 into a wealthy senatorial family in Rome and rose to become prefect of the city, its senior civil magistrate, by his early thirties. He resigned the office, converted his family's house on the Caelian Hill into a monastery, and gave the rest of his property to found six more monasteries in Sicily, entering the monastic life himself around 574. The papacy pulled him back into public affairs: Pope Pelagius II sent him to Constantinople as apocrisiarius, the papal representative at the imperial court, for about six years, and then made him one of his own deacons.
When Pelagius died of plague in 590, the Roman clergy and people elected Gregory as his successor. He reportedly tried to avoid the office, according to a later tradition even attempting to flee the city in a basket, but was found and installed. As pope he inherited a Rome cut off from a functioning imperial government by the Lombard invasions, and he effectively became the city's civil administrator as well as its bishop, organizing grain distribution, negotiating directly with the Lombard dukes, and managing the church's estates across Italy and Sicily through a systematic correspondence that survives in more than 850 letters, the largest body of papal correspondence to survive from antiquity.