Born of a Croatian father and a mother of the patrician Venetian family of Martinuzzi, György became a Paulist friar at the age of 28 after a brief military career. A skilled diplomat, he later became the close adviser to King John of Hungary in his struggle against the rival claims of Ferdinand (Ferdinand I) of Austria to the Hungarian throne.

Martinuzzi was in 1534 consecrated bishop of Nagyvárad in Transylvania. In 1538 he concluded with Ferdinand the Treaty of Nagyvárad, which left John with the royal title and most of Hungary and Ferdinand as successor to the Hungarian crown.

On his deathbed, however, John repudiated the treaty. The Turks recognized John Sigismund, the infant son of John, as king, but occupied Buda, the capital of Hungary; Martinuzzi, as guardian and regent, managed to retain Transylvania as an independent principality under Turkish suzerainty. Fighting off the intrigues of Isabella, the mother of John Sigismund, Martinuzzi returned to the original plan of unification of Hungary under the Austrian Habsburg dynasty in order to resist Turkish expansion. He finally concluded the agreement with Ferdinand in 1551, by which he continued to be governor of Transylvania and was rewarded with the archbishopric of Esztergom (Gran) and a cardinal's hat. To forestall attack by the Turks, Martinuzzi resumed payment of tribute to the Porte in December 1551. Ferdinand, however, suspected the cardinal's loyalty and had him killed.