Vigilius was Pope from 537 to 555. He belonged to a distinguished Roman family; his father Johannes is called consul, having received that title from the emperor. Reparatus, a brother of Vigilius, was a senator.

Vigilius was chosen by Pope Boniface II as his successor, but the opposition to such a procedure led Boniface in the following year to withdraw his designation of a successor and to burn the decree respecting it. The second successor of Boniface, Pope Agapetus I, appointed Vigilius papal representative at Constantinople. Empress Theodora sought to win him as a confederate, to revenge the deposition of the Monophysite Patriarch of Constantinople Anthimus, and also to gain aid for her efforts on behalf of the Monophysites. The empress promised Vigilius the Papal See and a large sum of money. After Agapetus's death, Vigilius returned to Rome equipped with letters from the Imperial Court. Meanwhile Silverius had been made pope through the influence of the King of the Goths. Soon after this the Byzantine commander Belisarius garrisoned Rome. Vigilius gave Belisarius the letters from Constantinople, which recommended Vigilius himself for the Papal See, causing Belisarius to depose Silverius. Owing to the pressure exerted by the Byzantine commander, Vigilius was elected pope in place of Silverius and consecrated and enthroned on March 29, 537. Silverius was put into Vigilius' keeping where the late pope soon died from the harsh treatment he received. After the death of his predecessor Vigilius was recognized as pope by all the Roman clergy.

It was not until the year 540 that Vigilius took a stand in regard to Monophysitism which he did in two letters sent to Constantinople. One of the letters is addressed to Emperor Justinian, the other to the Patriarch Menas. In both letters the pope supports positively the Synods of Ephesus and Chalcedon, and the decisions of his predecessor Pope Leo I, and throughout approves of the deposition of the Patriarch Anthimus.

In 544, Justinian ordered the Pope to Constantinople. Rome was now besieged by the Goths under Totila and the inhabitants fell into misery. Vigilius sent ships with grain but they were captured by the Goths. Vigilius reached Constantinople about the end of 546 or in January, 547.

Vigilius argued with the Emperor over Justinian's support of various heresies, and the Pope was held in Constantinople for eight years. In 555, the Emperor finally allowed Vigilius to return to Rome, but he died in Syracuse.