In 1647, Maidalchini's first cousin, Camillo Francesco Maria Pamphili, resigned his post as Cardinal-Nephew to marry and Innocent X required a new Cardinal Nephew.

Many of the responsibilities of the Cardinal-nephew had been previously delegated to the Secretary of State, Cardinal Giovanni Giacomo Panciroli, with the military duties assigned to the husbands of the Pope's two nieces.

[4] Girolamo Gigli wrote that Francesco's paternal aunt, Olimpia required him to reside with her at the Palazzo Pamphili in Piazza Navona rather than in the papal palaces, so as "not to lose her dominion", and to prevent his making independent decisions.

During his brief tenure as Cardinal-nephew, Cardinal Maidalchini was universally evaluated in a negative way by diplomatic observers, who saw in some of his misguided initiatives the hand of his aunt.

[4] In December 1649, Maidalchini obtained the privilege of opening the Holy Door at the Basilica di Santa Maria Maggiore, despite not yet having been ordained a priest.

In 1654 he was appointed Cardinal-Deacon of the Church of Santa Maria in Portico and the following year, following the death of his "uncle", he participated in the papal conclave of 1655 which elected Pope Alexander VII.

[5] Bargrave describes Maidalchini as, "being within an inch of an idiot" and recounts that the ladies of one congregation could not help but laugh at the appearance of a teenager in cardinal's vestments.

In 1666 Maidalchini was transferred to the deaconry of Santa Maria in Via Lata, which was customarily assigned to the senior Cardinal-Deacon, although it was only in 1669 when he assumed this position in the Sacred College.