Grandson of the Duke of Urbino, he spent most of his ecclesiastical career as a political operative, first for the Sforza in Milan, and then representing French interests.
During the sede vacante following the death of Innocent VIII, Sanseverino went to Rome, escorted by his brother Gaspare and a group of armed men, to demand his admission to the Sacred College and participation in the conclave.
Having assumed the title of Cardinal of S. Teodoro, he joined the Curia in the influential party of Ascanio Sforza, intent on averting the election of Giuliano Della Rovere, to the advantage of Rodrigo Borgia (Pope Alexander VI).
[5] His ecclesiastical ambitions were compromised, for some time, on the one hand, because relations had become tense between Rome and Milan and, on the other, due to the distrust of the curial circles towards him because of his reputation as a worldly man, dedicated to pleasures, to hunting and weapons, rather than to prayer.
[3] After the conquest of the Kingdom of Naples by the French, Sanseverino re-aligned with Ludovico il Moro, and supported an anti-French coalition.
He resumed managing relations between the French court and the Curia and was involved in the work of reconciling the Orsini and Colonna families, with the aim of keeping Alexander VI under pressure.
At the beginning of September, he followed the defeated duke in his hasty escape towards the imperial lands, but in February 1500 he himself led, with his brother Galeazzo and Cardinal Sforza, the Milanese troops to reconquer Milan.
[3] There was friction with Julius II over the possession of the Abbey of Chiaravalle, which the king had assigned to him, and his loyalty to France when the pope was reconciled with Venice in February 1510.
He participated with the French forces at the Battle of Ravenna (1512); Louis XII of France planned to make Cardinal Sanseverino governor of the Papal States after deposing the pope, but this never came to pass.
[3] The choice to support the French resulted in his excommunication and dismissal as cardinal by Julius II in January 1512, who redistributed his numerous benefits to other prelates.
On 25 June 1515 he was arrested on the pope's orders because it looked like one of his servants had killed a papal guard, but he proved his innocence the next day.