After Ranuccio's natural son and his potential rival, Ottavio, was relegated in a prison, he reigned initially under the regency of his uncle Odoardo Farnese and, after the latter's death, of his mother, Margherita Aldobrandini.

His first notable act as Duke was an alliance with France in 1633, a move designed to counter Spanish predominance in northern Italy and support his territorial ambitions.

In the absence of French assistance, Odoardo was convinced by Pope Urban VIII to sign a treaty of peace with Spain in 1637.

[1] His aggressive rule of Castro, a Farnese fief in the Papal States north of Rome, who the Barberini (Pope Urban's family) were eager to acquire, caused Odoardo to be excommunicated in 1641.

Although the Farnese fleet was destroyed and the Duke often proved recalcitrant, in the peace of 1644, the city of Castro was returned to him and Odoardo was reconciled with the Roman Catholic Church and readmitted to the Sacraments.