His sister Giovanna was married in 1478 to the municipal prefect, Giovanni della Rovere, a brother of Cardinal Giuliano, and in 1490 she bore him a daughter, Francesca Maria, a child who was looked upon as heir of Urbino.
Guidobaldo did not disdain to serve as a condottiere for pay and in the hope of winning honors; he was also a vassal of the Church.

Fear of the Borgias led him to seek their friendship although he hated them.
In the war against the Orsini the young Duke of Gandia was next in command under Guidobaldo, and Alexander made him the standard-bearer of the Church and Rector of Viterbo, and of the entire Patrimonium after he had removed Alessandro Farnese from that position.

This appears to have been due to a dislike he felt for Giulia's brother.

September 17, 1496, the Mantuan agent in Rome, John Carolus, wrote to the Marchioness Gonzaga: "Cardinal Farnese is shut up in his residence in the Patrimonium, and will lose it unless he is saved by the prompt return of Giulia." The same ambassador reported to his sovereign as follows: "Although every effort is made to conceal the fact that these sons of the Pope are consumed with envy of each other, the life of the Cardinal of S.Giorgio (Rafael Riario) is in danger; should he die, Caesar would be given the office of chancellor and the palace of the dead Cardinal of Mantua, which is the most beautiful in Rome, and also his most lucrative benefices.

Your Excellency may guess how this plot will terminate."[49] The war against the Orsini ended with the ignominious defeat of the papal forces at Soriano, January 23, 1497, whence Don Giovanni, wounded, fled to Rome, and where Guidobaldo was taken prisoner.