Born in Canino, Latium (then part of the Papal States), Farnese was the oldest son of Pier Luigi Farnese, Signore di Montalto (1435-1487) and wife Giovanna Caetani, descended from the Caetani family, which had also produced Pope Boniface VIII.
His first appointment to the cardinalate on December 18, 1534, was to his grandsons Alessandro Farnese and Ascanio Sforza, aged fourteen and sixteen years respectively; yet subsequent appointments included Gasparo Contarini, Sadoleto, Reginald Pole, and Giovanni Pietro Carafa, subsequently Pope Paul IV.
Paul III was in earnest in the matter of improving the ecclesiastical situation, and on June 2, 1536, he issued a papal bull convoking a general council to sit at Mantua in 1537. But at the very start the German Protestant estates declined to send any delegates to a council in Italy, while the duke of Mantua himself set down such large requirements that Paul III first deferred for a year and then discarded the whole project.
In 1536, Paul III invited nine eminent prelates, distinguished by learning and piety alike, to act in committee and to report on the reformation and rebuilding of the Church. In 1537 they turned in their celebrated Concilium de emendenda ecclesia (in J. le Plat, Monumenta ad historiam Concilii Tridentini, ii. 596–597, Leuven, 1782), exposing gross abuses in the Curia, in the church administration and public worship; and proffering many a bold and earnest word on behalf of abolishing such abuses. This report was printed not only at Rome, but at Strasburg and elsewhere.
But to the Protestants it seemed far from thorough; Martin Luther had his edition (1538) prefaced with a vignette showing the cardinals cleaning the Augean stable of the Roman Church with foxtails instead of brooms. Yet the Pope was in earnest when he took up the problem of reform. He clearly perceived that the emperor, Charles V would not rest until the problems were grappled in earnest, and a council was an unequivocal procedure that should leave no room for doubt of his own readiness to make changes. Yet it is clear that the Concilium bore no fruit in the actual situation, and that in Rome no results followed from the committee's recommendations.
On the other hand, serious political complications resulted. In order to vest his grandson Ottavio Farnese with the dukedom of Camerino, Paul forcibly wrestled the same from the duke of Urbino (1540). He also incurred virtual war with his own subjects and vassals by the imposition of burdensome taxes. Perugia, renouncing its obedience, was besieged by Paul's son, Pier Luigi, and forfeited its freedom entirely on its surrender. The burghers of Colonna were duly vanquished, and Ascanio was banished (1541). After this the time seemed ripe for annihilating heresy.
It was not foreseen at Rome in 1540, when the Church officially recognized the young society forming about Ignatius of Loyola, (founder of the Society of Jesus), what large results this new organization was destined to achieve; yet a deliberate and gradual course of action against Protestantism dates from this period. The second visible stage in the process becomes marked by the institution, or reorganization, in 1542, of the Holy Office (see Inquisition).
On another side, the Emperor was insisting that Rome should forward his designs toward a peaceable recovery of the German Protestants. Accordingly the Pope despatched Cardinal Morone as nuncio to Hagenau and Worms, in 1540; while, in 1541, Cardinal Contarini took part in the adjustment proceedings at the Conference of Regensburg. It was Contarini who led to the stating of a definition in connection with the article of justification in which occurs the famous formula "by faith alone are we justified," with which was combined, however, the Roman Catholic doctrine of good works. At Rome, this definition was rejected in the consistory of May 27, and Luther declared that he could accept it only provided the opposers would admit that hitherto they had taught differently from what was meant in the present instance.
The general results of the conference and the attitude of the Curia, including its rejection of Contarini's propositions, shows a definite avoidance of an understanding with the Protestants. All that could henceforth be expected of Paul was that he would co-operate in the violent suppression of heretics in Germany, as he had done in Italy, by creating an arm of the revived Inquisition for their annihilation.
Yet, even now, and particularly after the Regensburg Conference had proved in vain, the Emperor did not cease to insist on convening the council, the final result of his insistence being the Council of Trent, which, after several postponements, was finally convoked by the bull Laetare Hierusalem, March 15, 1545. Meanwhile, after the peace of Crespy (September, 1544), the situation had so shaped itself that Emperor Charles V (1519–56) began to put down Protestantism by force. Pending the diet of 1545 in Worms, the emperor concluded a covenant of joint action with the papal legate, Cardinal Alessandro Farnese. Paul III was to aid in the projected war against the German Evangelical princes and estates. The prompt acquiescence of Paul III in the war project was probably grounded on personal motives. The moment now seemed opportune for him, since the Emperor was sufficiently preoccupied in the German realm, to acquire for his son Pier Luigi the duchies of Parma and Piacenza. Although these belonged to the Papal States, Paul III thought to overcome the reluctance of the Cardinals by exchanging the duchies for the less valuable domains of Camerino and Nepi. The Emperor agreed, because of his prospective compensation to the extent of 12,000 infantry, 500 mounted troops, and considerable sums of money.
In Germany the campaign began in the west, where Protestant movements had been at work in the archbishopric of Cologne since 1542. The Reformation was not a complete success there, because the city council and the majority of the chapter opposed it; whereas on April 16, 1546, Hermann of Wied was excommunicated, his rank forfeited, and he was, in February, 1547, compelled by the Emperor to abdicate.
In the meantime open warfare had begun against the Evangelical princes, estates, and cities allied in the Schmalkaldic League (see Philip of Hesse). By the close of 1546, Charles V succeeded in subjugating South Germany, while the victory at the Battle of Muhlberg, on April 24, 1547, established his imperial sovereignty everywhere in Germany and delivered into his hands the two leaders of the league.
But while north of the Alps, in virtue of his preparations for the Augsburg Interim and its enforcement, the Emperor was widely instrumental in recovering Germany to Roman Catholicism, the Pope now held aloof from him because Charles V himself had stood aloof in the matter of endowing Pier Luigi with Parma and Piacenza, and the situation came to a total rupture when the imperial vice-regent, Ferrante Gonzaga, proceeded forcibly to expel Pier Luigi.
The Pope's son was assassinated at Piacenza, and Paul III believed that this had not come to pass without the emperor's foreknowledge. In the same year, however, and after the death of Francis I of France (1515–47), with whom the Pope had once again sought an alliance, the stress of circumstances compelled him to do the Emperor's will and accept the ecclesiastical measures adopted during the Interim. With reference to the assassinated prince's inheritance, the restitution of which Paul III demanded ostensibly in the name and for the sake of the Church, the Pope's design was thwarted by the Emperor, who refused to surrender Piacenza, and by Pier Luigi's heir in Parma, Ottavio Farnese.
In consequence of a violent altercation on this account with Cardinal Farnese, Paul III, at the age of eighty-one years, became so overwrought that an attack of sickness ensued from which he died, 10 November 1549.