His father, Litterio Ruffo, was a Calabrian aristocrat, holder of the title of duke of Baranello, while his mother, Giustiniana, was of the Roman family of Colonna.

Pietro Colletta, the historian of Naples, speaks of him as corrupt, and Jomini repeats the charge, but these can be dismissed as part of a hostile tradition, as they both participated in favour of France.

On 8 February 1799, he landed at La Cortona with a small following, and began to raise the so-called "army of the faith" in association with Michele Pezza, "Fra Diavolo", and other brigand leaders.

Backed by the Russian fleet of Admiral Ushakov, Ruffo had no difficulty in upsetting the Parthenopean Republican government established by the French, and by June had advanced to Naples.

In the meantime Rear-Admiral Horatio Nelson, sent from Palermo by King Ferdinand, appeared in the Bay of Naples with his fleet; he called the cardinal to task for his leniency, and revoked the terms of surrender.

They formed the Christian and Real Army, also known as Esercito della Santa Fede in Nostro Signore Gesù Cristo, and conquered Crotone moving to the Basilicata and Apulia regions (Altamura and Modugno), and finally in the Principato Ultra.

The following day, when the first Jacobins were waiting to be boarded, the English admiral informed that the pact of pacification partially enacted by the cardinal, was "infamous" and that he would never allow its execution.

He resigned the vicar-generalship, which he had been granted on 25 January 1800, to the prince of Cassero, and during the second French occupation and the reigns of Joseph Bonaparte and Joachim Murat he lived quietly in Naples.

After the conquest of Naples, Ruffo decided to send some military companies within the Roman Republic, led by the general Gian Battista Rodio.

After the defeat of the Roman Republic, on 11 August 1800 Ruffo entered in the Urbe and changed his cardinal diacony with the one of Santa Maria in Cosmedin.

After this gesture, he become part of the so-called "red cardinals", a restricted circle of high prelates who weren't punished by the French emperor and got the right to continue to publicly profess their religious functions.

On 8 February 1815 Pope Pius VII recalled Ruffo to Rome and appointed him Prefect of the Annona and of Grascia, a role responsible for the procurement of meat, fat, and oil.