As a member of the Aragonese court, he reconciled King Alfonso V with Pope Martin V, who appointed (1429) Calixtus bishop of Valencia. Pope Eugenius IV made him cardinal in 1444.

As a compromise between the influential Colonna and Orsini families of Rome, Borgia was chosen pope on April 8, 1455. (He was thought unlikely to reign long in view of his advanced age.) Calixtus made a crusade to recover Constantinople (now Istanbul) from the Turks the first order of his pontificate, but he failed despite heroic efforts. He was successful, however, in raising a pontifical fleet that relieved many of the Aegean islands.

The repulse of the Turks from Belgrade on Aug. 6, 1456, was commemorated by Calixtus when he instituted the Feast of the Transfiguration (Transfiguration, Feast of the) (1457), ordering that it be observed on that day. His pontificate revised St. Joan of Arc (Joan of Arc, Saint)'s trial by proclaiming her innocence. His personal life was blameless, but his nepotism was widely resented. Following the fashion of his time, he showered favours on his nephew, Rodrigo Borgia, whom he made cardinal and generalissimo of the papal forces and who later became Pope Alexander VI.