Margherita's father enjoyed special confidence in the pontiff, who bestowed on him the titles of Count of Sarsina and Meldola (later elevated to the rank of Prince in 1597), and her mother was his favorite niece.

[2] As suitors for Margherita, the Pope considered the candidacies of princes from the Houses of Savoy and Medici, and even King Henry IV of France.

The marriage agreement was signed in Rome with the active participation of Spanish diplomats and Cardinals Pietro Aldobrandini and Odoardo Farnese.

It is believed that the wedding of the Duke and the grand-niece of the Pope inspired the cycle of frescos called The Loves of the Gods, a work of the Bolognese artist Annibale Carracci and his studio, which is located in the west wing of the Palazzo Farnese in Rome.

[2] The Duchess couldn't get pregnant for a long time; she had several miscarriages and the first two children she gave birth to in the first ten years of her marriage, in 1602 and 1603, only lived for a few hours.

The question of the probable infertility of the then bride of the Duke of Parma was also known by his younger brother Cardinal Odoardo Farnese, who, nevertheless, didn't inform the groom.

[2][3] In 1610, Margherita finally gave birth a child who survived, a son, named Alessandro after his paternal grandfather, and who momentarily raised the hopes of the court.

After numerous attempts to correct the boy's condition, in 1618 his inability to govern the state was officially declared; the heir of the Ducal throne of Parma was the second surviving son, Odoardo, born in 1612.

[4] To the delight of Margherita, the illegitimate Ottavio Farnese was removed from court; unsatisfied with the loss of his position of heir, he became a member of a conspiracy against his father, which was revealed, after which he was also imprisoned in the Rocchetta prison until his death.

Only once during the years of marriage did the Duchess travel with her husband outside Parma: in 1620, they paid an official visit to Piacenza, where they attended the unveiling of the equestrian monuments of the Duke and his father Alessandro Farnese.