Cornelius was elected pope on either March 6 or March 13, 251 during the lull in the persecution of the emperor Decius. His election was opposed by Novatian, who maintained the view that not even the bishops could grant remission for grave sins like murder, adultery, and apostasy, but that these could only be remitted at the Last Judgement; Cornelius on the contrary believed that bishops could grant remission for these grave sins. With the help of St Cyprian, his party prevailed and he was elected Pope. Novatian fled Rome, but his followers organized into a sect considered heretical by the rest of Christianity.

After ruling for two years, under the emperor Trebonianus Gallus, he was exiled to Centuricellae (Civita Vecchia), where he died. He is commemorated with Cyprian on September 16, which is not, however the anniversary of his death. He died in June 253.