Despite the rampant nepotism that was to later define papal politics of the 17th century, Borghese received no particular benefits from his great uncle Pope Paul V whose reign continued until 1621.

Maffeo Barberini, however, was raised to the cardinalate by Pope Paul and felt a need to recognise the Borghese family with a similar honour.

When he was elected to the papal throne as Pope Urban VIII in 1623, he set about repaying those who had advanced his own career.

So it was that Borghese was elevated to Cardinal by Pope Urban VIII the following year, on 7 October 1624 and was appointed cardinal-deacon of the church of San Giorgio in Velabro.

In 1633 he was appointed Cardinal-protector of Flanders and he opted for the title of the San Crisogono pro illa vice deaconry in 1636.