The Wars of Castro are renewed in 1649, when the son and successor of Odoardo Farnese, Duke of Parma and Piacenza, who controlled the city, refuses to pay back Roman creditors as his father had agreed to in the treaty signed five years prior.

Duke Ranuccio II, who had succeeded to the title September 11, 1646, also refuses to recognize the new bishop of Castro appointed by Pope Innocent X.

When the bishop, Monsignor Cristoforo Giarda, is killed en route to Castro, near Monterosi, Pope Innocent X accuses Ranuccio of murdering him.

In retaliation for this alleged crime, forces under the pope march on Castro on September 2, and on the pope's orders completely destroy the city.

Duke Ranuccio is forced to cede control of the territories around Castro back to the pope, who now tries to use the land to settle accounts with the Duke's creditors.

This marks the end of the second war of Castro, and the final demise of the city, as it will never be rebuilt.