Fabian became Bishop of Rome around 236 and served for fourteen years during a period of relative peace for the Church. He oversaw the organization of Rome's catacomb burials, systematized charitable works among the clergy and widows, and maintained ecclesiastical order during the relative stability of the later Severan dynasty. When the Emperor Decius (249–251) issued an edict requiring all subjects to participate in pagan sacrifice and obtain certificates of compliance, Fabian became a marked target.

According to the Depositio Martyrum (354), a contemporary Roman martyrology compiled from official records, Fabian was arrested in 250 and executed by the sword (the traditional Roman method for citizens). Eusebius of Caesarea (Ecclesiastical History VI.29, 39) provides the principal patristic account, noting that Fabian died at the beginning of the Decian persecution and earned distinction among martyrs. Cyprian, writing from Carthage in his Letter 9, explicitly mentions Fabian's martyrdom with evident admiration, describing him as a model of episcopal steadfastness.

Fabian's short pontificate ended under extraordinary circumstances: he was among the first major ecclesiastical figures to fall to the persecution. His status as a bishop gave him prominence within the Church and made him an obvious target for imperial authority seeking to decapitate Christian leadership. The Decian persecution would eventually claim tens of thousands of Christians and forced the Church to grapple with the theological and pastoral question of how to treat those who had lapsed during the crisis.

Traditionally, Fabian was buried in the Catacomb of Callixtus, where his tomb was venerated. Later hagiography embellished his death with supernatural elements (light appearing at his grave, miraculous healings), but the core historical account is reliable.