Callixtus I (also Callistus I) was pope from about 217 to 222, during the reigns of the Emperors Heliogabalus and Severus. Hippolytus, his contemporary, suggests that when Callixtus, as a young slave was put in charge of a bank by his master, Carpophorus, he lost the money deposited by other Christians. Callixtus then fled from Rome, but was caught near Portus . According to the tale, Callixtus jumped overboard to avoid capture, but was rescued and taken back to his master. He was released at the request of the creditors, who hoped he might be able to recover some of the money, but was rearrested for fighting in a synagogue when he tried to borrow or collect debts from some Jews. Denounced as a Christian, Callixtus was sentenced to work in the mines of Sardinia. Finally, he was released with other Christians at the request of Marcia, a mistress of Emperor Commodus. His health was so weakened that his fellow Christians sent him to Antium to recuperate and he was given a pension by Pope Victor I.

Callixtus established the practice of the absolution of all repented sins. Hippolytus was especially upset by the pope's admitting to communion those who had repented for murder, adultery, and fornication. A spot on which he had built an oratory was claimed by tavern keepers, but the Emperor decided that the worship of any god was better than a tavern. This is said to have been the origin of Santa Maria in Trastevere. In fact the Church of St Callistus is close by, containing a well into which legend says his body was thrown, and this is probably the church he built, rather than the more famous basilica.

It is possible that Callixtus was martyred around 222, perhaps during a popular uprising, but the legend that he was thrown down a well has no historical foundation. He is honored as a martyr in Todi, Italy, on August 14. He was buried in the cemetery of Calepodius on the Aurelian Way. His relics were transferred to Santa Maria in Trastevere in the ninth century.