He participated at the Congress of Ferrara in 1526 as the Republic's representative; at the Congress the League of Cognac was formed against the Emperor, allying France with Venice and several states of Italy. Later, after the Sack of Rome (1527), he assisted in reconciling the emperor and Clement VII, whose release he obtained and with the Republic of Bologna. He was made Governor of Brescia and Venice's representative at the Holy See, where, though he was unsuccessful in retaining the cities of Ravenna and Cervia that had been seized during the invasion of the Connetable de Bourbon, on his return to Venice wasd made a senator and a member of the Great Council.
In 1535, Paul III unexpectedly made the secular diplomat a cardinal in order to bind an able man of evangelical disposition to the Roman interests. Contarini accepted, but in his new position did not exhibit his former independence. At the time he was promoted to cardinal, May 21, 1535, he was still a layman. One of the fruits of his diplomatic activity is his De magistratibus et republica Venetorum.
As Cardinal, Contarini figured among the most prominent of the Spirituali, the leaders of the movement for reform within the Roman church. In April 1536 Paul III appointed a commission to devise ways for a reformation, with Contarini presiding. Paul III received favorably Contarini's Consilium de Emendanda Ecclesia, which was circulated among the cardinalate, but it remained a dead letter. Contarini in a letter to his friend Reginald Cardinal Pole (dated 11 November 1538) says that his hopes had been wakened anew by the pope's attitude. He and his friends, who formed the Catholic evangelical movement of the Spirituali, thought that all would have been done when the abuses in church life had been put away. What Contarini had to do with it is shown by his letters to the pope in which he complained of the schism in the church, of simony and flattery in the papal court, but above all of papal tyranny, its least grateful passages. Paul's successor Paul IV, once a member on the commission, in 1539 put it on the Index Librorum Prohibitorum.
In 1541 Cardinal Contarini was papal delegate at the Conference of Regensburg, the diet and religious debate marking the culmination of attempts to restore religious unity in Germany by means of conferences. There everything was unfavorable; the Catholic states were bitter, the Evangelicals were distant. Contarini's instructions though apparently free were in fact full of papal reservations. But the papal party had gladly sent him, thinking that through him a union in doctrine could be brought about, while the interest of Rome could be attended to later. Though the princes stood aloof, the theologians and the emperor were for peace, so the main articles were put forth in a formula, Evangelical in thought and Catholic in expression. The papal legate had revised the Catholic proposal and assented to the formula agreed upon. All gave their approval, even Johann Eck, though he later regretted it.
Contarini's theological advisor was Tommaso Badia; his own position is shown in a treatise on justification, composed at Regensburg, which in essential points is Evangelical, differing only in the omission of the negative side and in being interwoven with the teaching of Aquinas. Meanwhile the papal policy had changed, and Contarini was compelled to follow his leader. He advised the emperor, after the conference had broken up, not to renew it, but to submit everything to the pope.
Ignatius Loyola acknowledged that Cardinal Contarini was largely responsible for the papal approbation of the Society of Jesus, on September 27, 1540. Meanwhile Rome had drifted further into reaction, and Contarini died while legate at Bologna, at a time when the Inquisition had driven many of his friends and fellows in conviction into exile.
The Catholic Encyclopedia reports that his accomplishments, but still more his mild resoluteness and blameless character, made him respected everywhere.