Born in Florence, he was raised with his brothers Piero and Giovanni di Lorenzo de' Medici, who became Pope Leo X; as well as his cousin Giulio de' Medici, who became Pope Clement VII.

His older brother Piero was briefly the ruler of Florence after Lorenzo's death, until the republican faction drove out the Medici in 1494.

The Medici family was restored to power after the Holy League drove the French forces that had supported the Florentine republicans from Italy.

He married Filiberta (1498–1524), daughter of Philip II, Duke of Savoy, on 22 February 1515 at the court of France,[1] thanks to the intercession of his brother Giovanni, now pope as Leo X, in the same year that King Francis I of France (Filiberta's nephew) invested him with the title Duke of Nemours (which had recently reverted once again to the French crown) on the occasion.

Giuliano left a single illegitimate son, Ippolito de' Medici, who became a cardinal.