He was born in Florence one month after his father's death. His father, Giuliano de' Medici, had been assassinated. Although his parents had not had a formal marriage, a canon law loophole allowing for the parents to have been betrothed per sponsalia de presenti meant that Giulio was considered legitimate. He was thus the nephew of Lorenzo the Magnificent, who educated him in his youth. Clement's mother, Fioretta Gorini, also died leaving him an orphan.

Giulio was made a Knight of Rhodes and Grand Prior of Capua, and, upon the election of his cousin Giovanni de' Medici to the pontificate as Leo X (1513 – 21), he soon became a powerful figure in Rome. Upon his cousin's accession to the papacy, Giulio became his principal minister and confidant, especially in the maintenance of the Medici interest at Florence as archbishop of that city. On 23 September 1513, he was made cardinal and he was consecrated on 29 September. He had the credit of being the main director of papal policy during the whole of Leo X's pontificate, especially as cardinal protector of England. He was also the titular Bishop of Worcester in the county of Worcestershire in England as Administrator or the See of Worcester.

At Leo X's death in 1521, Cardinal Medici was considered especially papabile in the protracted conclave. Although unable to gain the Papacy for himself or his ally Alessandro Farnese (both preferred candidates of Emperor Charles V (1519 – 56)), he took a leading part in determining the unexpected election of the short lived Pope Adrian VI (1522 – 23), with whom he also wielded formidable influence. Following Adrian VI's death on 14 September 1523, Medici finally succeeded in being elected Pope Clement VII in the next conclave (19 November 1523).

He brought to the papal throne a high reputation for political ability and possessed in fact all the accomplishments of a wily diplomat. However, he was considered worldly and indifferent to the perceived dangers of the Protestant Reformation by the people of the papacy.

At his accession, Clement VII sent the Archbishop of Capua, Nikolaus von Schönberg, to the Kings of France, Spain, and England, in order to bring the war then raging in Europe to a peace. But his attempt failed.

Francis I of France's conquest of Milan in 1524 prompted the Pope to quit the Imperial – Spanish side and to ally himself with other Italian princes, including the Republic of Venice, and France in the January of 1525. This treaty granted the definitive acquisition of Parma and Piacenza for the Papal States, the rule of Medici over Florence and the free passage of the French troops to Naples. This policy in itself was sound and patriotic, but Clement VII's zeal soon cooled; by his want of foresight and unseasonable economy, he laid himself open to an attack from the turbulent Roman barons, which obliged him to invoke the mediation of the emperor. One month later, however, Francis I was crushed and imprisoned in the Battle of Pavia, and Clement VII veered back to his former engagements with Charles V, signing an alliance with the viceroy of Naples.

But he was to change sides again when Francis I was freed after the Treaty of Madrid (1526): the Pope entered into the League of Cognac together with France, Venice, and Francesco Sforza of Milan. Clement VII issued an invective against Charles V, who in reply defined him a "wolf" instead of a "shepherd", menacing the summoning of a council about the Lutheran question.

In his bull "Intra Arcana" he advocated a militaristic means of evangelizing "by force and arms, if needful" which contrasts with the more peaceful admonitions of his successor Paul III in his bull "Sublimus Dei".

The oldest indult which Benedict XIV quotes in this connection is that granted by Clement VII to the Dominicans of the Convent of Forlì, 25 January 1526, to celebrate the Mass of Blessed James Salomonio "as often during the year as their devotion may move them to do so" (De canonizatione de SS.).

—Camillus Beccari

The Pope's wavering politics also caused the rise of the Imperial party inside the Curia: Cardinal Pompeo Colonna's soldiers pillaged Vatican Hill and gained control of the whole of Rome in his name. The humiliated Pope promised therefore to bring the Papal States to the Imperial side again. But soon after, Colonna left the siege and went to Naples, not keeping his promises and dismissing the Cardinal from his charge. From this point on, Clement VII could do nothing but follow the fate of the French party to the end.

Soon he found himself alone in Italy too, as the duke of Ferrara had sided with the Imperial army, allowing the horde of Landsknechts led by Charles III, Duke of Bourbon and Georg von Frundsberg to reach Rome without harm.

Charles of Bourbon died while mounting a ladder during the short siege and his starving troops, unpaid and left without a guide, felt free to ravage Rome from 6 May 1527. The many incidents of murder, rape, and vandalism that followed ended the splendors of Renaissance Rome forever. Clement VII, who had displayed no more resolution in his military than in his political conduct, was shortly afterwards (June 6) obliged to surrender himself together with the castle of Sant' Angelo, where he had taken refuge. He agreed to pay a ransom of 400,000 ducati in exchange for his life; conditions included the cession of Parma, Piacenza, Civitavecchia, and Modena to the Holy Roman Empire. (Only the last could be occupied in fact.) At the same time, Venice took advantage of his situation to capture Cervia and Ravenna while Sigismondo Malatesta returned in Rimini.

Clement was kept as a prisoner in Castel Sant' Angelo for six months. After having bought off some Imperial officers, he escaped disguised as a peddler and took shelter in Orvieto and then in Viterbo. He came back to a depopulated and devastated Rome only in October 1528.

Meanwhile, in Florence, Republican enemies of the Medici took advantage of the chaos to again expel the Pope's family from the city.

In June of the next year the warring parties signed the Peace of Barcelona. The Papal States regained some cities, and Charles V agreed to restore the Medici to power in Florence. In 1530, after an eleven month siege, the Tuscan city capitulated, and Clement VII installed his illegitimate son Alessandro as duke. Subsequently the Pope followed a policy of subservience to the emperor, endeavoring on the one hand to induce him to act with severity against the Lutherans in Germany and on the other to avoid his demands for a general council.

Clement's dependence on Charles V led indirectly to the break between the Kingdom of England and the Catholic Church. By the late 1520s, King Henry VIII wanted to have his marriage to Catherine of Aragon annulled. The royal couple had not produced a male heir who survived into adulthood, and Henry wanted a son to secure the Tudor dynasty. Henry claimed that this lack of a male heir was because his marriage was "blighted in the eyes of God". Catherine had been his late brother's wife, and it was therefore against Biblical teachings for Henry to have married her. Indeed, a special dispensation from Pope Julius II had been needed to allow the wedding in the first place. Henry argued that this had been wrong and that his marriage had never been valid. In 1527 Henry asked Pope Clement to annul the marriage, but the Pope refused. According to canon law, the Pope cannot annul a marriage on the basis of a canonical impediment previously dispensed. Clement also feared the wrath of Catherine's nephew, Charles V, whose own troops were responsible for the episode earlier that year that included the sack of Rome. In the matter of the annulment, no progress seemed possible: the Pope seemed more afraid of Emperor Charles V than of Henry. Many people close to Henry VIII wished simply to ignore the Pope; but in October 1530 a meeting of clergy and lawyers advised that the English Parliament could not empower the Archbishop of Canterbury to act against the Pope's prohibition. In Parliament, Bishop John Fisher was the Pope's champion.

Henry was married to Anne Boleyn at some debated point between the end of 1532 and the beginning of 1533. One 16th century chronicler put the wedding service on the feast of Saint Erkenwald in Dover Castle, around November 14, whilst others have suggested a second or perhaps sole Nuptial Mass at the Palace of Whitehall in Westminster on January 25, 1533. The name of the celebrant is unknown, although various sources suggest it was Father Rowland Lee, future Bishop of Lichfield, or Prior George Browne, future Archbishop of Dublin. The marriage was made easier by the death of Archbishop William Warham, a stalwart friend of the Pope, after which Henry persuaded Clement to appoint Father Thomas Cranmer, a friend of the Boleyn family, as his successor as Archbishop of Canterbury. The Pope granted the papal bulls necessary for Cranmer’s promotion to Canterbury, as Henry had personally financed them. Cranmer was prepared to grant the annulment of the marriage to Catherine as Henry required. Anne gave birth to a daughter, Princess Elizabeth, three months after her public coronation as queen in Westminster Abbey. The Pope responded to the marriage by excommunicating both Henry and Cranmer from the Catholic Church. For some time, the news was kept from the new queen, for fear it would bring about a miscarriage.

Consequently in England, in the same year, the Act of First Fruits and Tenths transferred the taxes on ecclesiastical income from the Pope to the English Crown. The Peter's Pence Act outlawed the annual payment by landowners of one penny to the Pope. This act also reiterated that England had "no superior under God, but only your Grace" and that Henry's "imperial crown" had been diminished by "the unreasonable and uncharitable usurpations and exactions" of the Pope. Ultimately Henry led the English Parliament to pass the Act of Supremacy (1534) that established the independent Church of England and breaking from the Catholic Church.

During his half - year imprisonment in 1527, Clement VII grew a full beard as a sign of mourning for the sack of Rome. This was a violation of Catholic canon law, which required priests to be clean - shaven; however, it had the precedent of the beard which Pope Julius II had worn for nine months in 1511 – 12 as a similar sign of mourning for the loss of the papal city of Bologna.

Unlike Julius II, however, Clement VII kept his beard until his death in 1534. His example in wearing a beard was followed by his successor, Paul III, and indeed by twenty - four popes who followed him, down to Innocent XII, who died in 1700. Clement VII was thus the unintentional originator of a fashion that lasted well over a century.

In 1533, Johann Widmanstetter (alternately spelled John Widmanstad), a secretary of Pope Clement VII, explained the Copernican system to the Pope and two cardinals. The Pope was so pleased that he gave Widmanstetter a valuable gift.

Towards the end of his life, Clement VII once more gave indications of a leaning towards a French alliance, which was averted by his death in September 1534 in Rome after consuming the death cap mushroom. He was buried in Santa Maria sopra Minerva.

As for the arts, Clement VII is remembered for having ordered, just a few days before his death, Michelangelo's painting of The Last Judgment in the Sistine Chapel.