Sixtus II was elected Bishop of Rome on 31 August 257. Before him, Rome had quarrelled sharply with the Churches of Africa and Asia Minor over rebaptising heretics. Sixtus, called 'a good and peaceful priest', restored friendly relations while keeping the Roman practice.

In early August 258 Emperor Valerian ordered bishops, priests and deacons put to death at once. On 6 August Sixtus gathered his people in the little-known cemetery of Praetextatus on the Appian Way. As he sat in his chair addressing them, soldiers seized him. He was beheaded, probably after a brief trial, and four deacons died with him.

Pope Damasus later placed an inscription on his tomb in the cemetery of Callistus. He is the Xystus named in the Canon of the Mass.

Dionysius of Alexandria wrote letters to S. Sixtus on the disputed subject, marked by a tone of moderation, and a desire for peace and the truth. With respect to his own practice, he mentioned that he did not baptize persons who returned to the Church, after having once belonged to it, and having fallen into heresy; and he stated that he had received this custom from his predecessor Heracles. He also wrote to Sixtus, asking for his advice in the case of a man who had been a member of the Alexandrian Church for above twenty years, but who was now suffering great scruples because he had not been baptized according to the forms of the Catholic Church.

Elected 31 Aug., 257, martyred at Rome, 6 Aug., 258. His origin is unknown. The "Liber Pontificalis" says that he was a Greek by birth, but this is probably a mistake, originating from the false assumption that he was identical with a Greek philosopher of the same name, who was the author of the so-called "Sentences" of Xystus. During the pontificate of his predecessor, St. Stephen, a sharp dispute had arisen between Rome and the African and Asiatic Churches, concerning the rebaptism of heretics, which had threatened to end in a complete rupture between Rome and the Churches of Africa and Asia Minor (see SAINT CYPRIAN OF CARTHAGE). Sixtus II, whom Pontius (Vita Cyprian, cap. xiv) styles a good and peaceful priest (bonus et pacificus sacerdos), was more conciliatory than St. Stephen and restored friendly relations with these Churches, though, like his predecessor, he upheld the Roman usage of not rebaptizing heretics.

Shortly before the pontificate of Sixtus II the Emperor Valerian [Roman emperor 253–260, who persecuted bishops and clergy] issued his first edict of persecution, which made it binding upon the Christians to participate in the national cult of the pagan gods and forbade them to assemble in the cemeteries, threatening with exile or death whomsoever was found to disobey the order. In some way or other, Sixtus II managed to perform his functions as chief pastor of the Christians without being molested by those who were charged with the execution of the imperial edict. But during the first days of August, 258, the emperor issued a new and far more cruel edict against the Christians, the import of which has been preserved in a letter of St. Cyprian to Successus, the Bishop of Abbir Germaniciana (Ep. lxxx). It ordered bishops, priests, and deacons to be summarily put to death ("episcopi et presbyteri et diacones incontinenti animadvertantur"). Sixtus II was one of the first to fall a victim to this imperial enactment ("Xistum in cimiterio animadversum sciatis VIII. id. Augusti et cum eo diacones quattuor"-Cyprian, Ep. lxxx). In order to escape the vigilance of the imperial officers he assembled his flock on 6 August at one of the less-known cemeteries, that of Prætextatus, on the left side of the Appian Way, nearly opposite the cemetery of St. Callistus. While seated on his chair in the act of addressing his flock he was suddenly apprehended by a band of soldiers. There is some doubt whether he was beheaded forthwith, or was first brought before a tribunal to receive his sentence and then led back to the cemetery for execution. The latter opinion seems to be the more probable.

The inscription which Pope Damasus (366-84) placed on his tomb in the cemetery of St. Callistus may be interpreted in either sense. The entire inscription is to be found in the works of St. Damasus (P.L., XIII, 383-4, where it is wrongly supposed to be an epitaph for Pope Stephen I), and a few fragments of it were discovered at the tomb itself by de Rossi (Inscr. Christ., II, 108). The "Liber Pontificalis" mentions that he was led away to offer sacrifice to the gods ("ductus ut sacrificaret demoniis"-I, 155). St. Cyprian states in the above-named letter, which was written at the latest one month after the martyrdom of Sixtus, that "the prefects of the City were daily urging the persecution in order that, if any were brought before them, they might be punished and their property confiscated". The pathetic meeting between St. Sixtus II and St. Lawrence, as the former was being led to execution, of which mention is made in the unauthentic "Acts of St. Lawrence" as well as by St. Ambrose (Officiorum, lib. I, c. xli, and lib. II, c. xxviii) and the poet Prudentius (Peristephanon, II), is probably a mere legend. Entirely contrary to truth is the statement of Prudentius (ibid., lines 23-26) that Sixtus II suffered martyrdom on the cross, unless by an unnatural trope the poet uses the specific word cross (" Jam Xystus adfixus cruci") for martyrdom in general, as Duchesne and Allard (see below) suggest. Four deacons, Januarius, Vincentius, Magnus, and Stephanus, were apprehended with Sixtus and beheaded with him at the same cemetery. Two other deacons, Felicissimus and Agapitus, suffered martyrdom on the same day. The feast of St. Sixtus II and these six deacons is celebrated in the Roman Rite on 7 August, the day after their martyrdom. The remains of Sixtus were transferred by the Christians to the papal crypt in the neighbouring cemetery of St. Callistus. Behind his tomb was enshrined the bloodstained chair on which he had been beheaded. An oratory (Oratorium Xysti) was erected above the cemetery of St. Prætextatus, at the spot where he was martyred, and was still visited by pilgrims of the seventh and the eighth century.