As Viceroy of Sicily and Naples, Osuna reorganized the local administration and armadas with new strategies and ships, and implemented a highly profitable and successful privateering system against the Ottoman Empire, the Republic of Venice and the Barbary pirates.

[2] Osuna was eventually deposed in 1620, undoing much of his work, in midst of the political unstability caused by the fall of the royal minister Francisco de Sandoval, Duke of Lerma.

But this, as many other pieces of information, anecdotes, speeches and stories of Leti's biography are doubtful nowadays; the same happens with his alleged participation, in the royal expedition to Zaragoza to put down the Aragonese revolt in 1588 as by then he was only aged 13.

In 1602, apparently with the agreement of Juan Fernández de Velasco, 5th Duke of Frías, Constable of Castile, his uncle and political godfather and one of the most powerful and outstanding personalities of the reign of King Philip III of Spain, Osuna escaped from his confinement in the castle of Cuéllar, a place/prison used for the last two centuries to control "illustrious" Crown guests accompanied by a servant, arriving in Brussels in October of that year.

In 1602 and 1603 he had a role in controlling and defusing the mutinies which erupted in Brabant among the armies of the Archduke, even financing the arrangements with the mutineers with his own money, raised in Flanders with the guarantee of his Spanish properties.

In 1616, the commander of the royal Sicilian fleet, Francisco de Rivera y Medina, achieved another important victory against Turkish galleys in the Battle of Cape Celidonia.

In May 1618 the Venetian authorities claimed to have uncovered a very serious conspiracy to sack the city and burn the arsenal, summarily executing a number of alleged participants (all of them French) but insinuating that the real and secret heads of the plot were Osuna and the Spanish ambassador to Venice, the Marquis of Bedmar.

A few days after Philip III's death, in 1621, in a 'purge' by the ministers of the new and very young king against Lerma's family and friends, Osuna was arrested by a decision of the State Council – the highest political and administrative body of the Spanish Monarchy – on a large and wide-ranging array of accusations (corruption, but also impiety, sexual misconduct, etc.).

No sentence was ever pronounced, but the House of Osuna was out of the royal favour for three decades, and only during the reign of Charles II did it again play an important role in Spanish political life.