Born in Florence, he was recognized by the majority of his contemporaries as the only son of Lorenzo II de' Medici (grandson of Lorenzo de' Medici "the Magnificent"). A few believed him to be in fact the illegitimate son of Giulio de' Medici (later Pope Clement VII), nephew of Lorenzo the Magnificent, but at the time that was a minority view.
Alessandro's nickname "il Moro" ("the Moor") is said to derive from his features. Some historians (such as Christopher Hibbert) believe he had been born to a servant of African descent who was working in the Medici household, identified in documents as Simonetta da Collevecchio. The French author Jean Nestor, writing in the 1560s, reported that the claim of a Moorish slave origin was a false rumor first spread by Alessandro's exiled enemies in Naples.
The Emblem of Alessandro de' Medici
, based on Dürer's Rhinoceros
, with the motto "Non buelvo sin vencer" (old Spanish for "I shall not return without victory").
(From Paolo Giovio's Dialogo dell'impresse militari et amorosi
When Emperor Charles V sacked Rome in 1527, a faction of Florentines took advantage of the turmoil in Italy to reinstall the Florentine Republic. Both Alessandro and Ippolito de' Medici fled, along with most of the Medici and their main supporters, including Cardinal Silvio Passerini, (the regent for young Alessandro and Ippolito, and de facto ruler of Florence for Pope Clement VII). Eight-year-old Catherine de' Medici was left behind. Michelangelo, then occupied in creating a funerary chapel for the Medici, initially took charge of building fortifications around Florence in support of the Republic; however, he later fled the city, fearing retribution. Eventually Clement made his peace with the Emperor, and in the summer of 1530, following a lengthy siege supported by Imperial troops, the Medici were restored to power.
In 1530, Clement VII assigned Florence to nineteen-year-old Alessandro, choosing him for the position over Ippolito (the latter was made a cardinal). In the meantime, Alessandro had become Duke of Penne, an appointment purchased from the Emperor. He arrived in Florence to take up his rule on 5 July 1531, and 9 months later was made hereditary Duke of Florence by Charles V (as Tuscany lay outside the Papal States). This signaled the end of the Republic. 
Alessandro's many enemies among the Florentine exiles declared that his rule was harsh, depraved and incompetent, an assessment debated by historians. One relic of his rule sometimes pointed out as a symbol of oppression is the massive Fortezza da Basso, a fortress that is today the largest historical monument of Florence. In 1535, the Florentine opposition sent his cousin Ippolito to appeal to Emperor Charles V against some actions of the duke, but Ippolito died en route. Rumors spread that he had been poisoned at Alessandro's orders.
In a late replay of the kind of medieval civil politics that had long revolved around pope and emperor, commune and lord, Emperor Charles V supported Alessandro against the Florentine exiles. In 1536, Charles V married his natural daughter Margaret of Austria to Alessandro. For his own inclinations, Alessandro seems to have remained faithful to one mistress, Taddea Malaspina, who bore his only children: Giulio de' Medici (c. 1533/37-1600), who also had illegitimate issue, and Giulia de' Medici.