In 1978, while waiting for a bus to take him to university so that he could undergo an algebra exam, Pannofino heard the sound of gunshots coming from a street nearby: what he heard was in fact Aldo Moro being kidnapped;[1] he would later write a song based on those events, Il sequestro di stato (i.e. State abduction),[2] which appears in the soundtrack of Felice Farina's 2014 film Patria featuring him in the main role.

Pannofino began his career as a theatre actor at some point between the late 1970s and the early 1980s and as a screen actor during the mid-90s, appearing in many films and television series through the years;[3] these include Giovanni Falcone – L'uomo che sfidò Cosa Nostra, in which he portrayed real life gangster Tommaso Buscetta, and Night Bus, starring Giovanna Mezzogiorno and Valerio Mastandrea, as well as the TV film Imperium: Pompeii.

Other actors he often or occasionally dubs include Kurt Russell, Wesley Snipes, Mickey Rourke, Dan Aykroyd, Antonio Banderas, Jean-Claude Van Damme, Philip Seymour Hoffman, Ray Winstone, Michael Madsen, Kiefer Sutherland, Daniel Day-Lewis and Kevin Spacey (the latter of which is mainly dubbed by Roberto Pedicini).

In his animated roles, he performed the Italian voices of Papi in the Beverly Hills Chihuahua film series, The Red Guy in Cow and Chicken and I Am Weasel, Lrrr in the first five seasons of Futurama and many more.

[9] He is a fan of Lazio, a passion that he developed in the mid-70s when, as a teenager, he sold drinks in the stands of the Olympic stadium in Rome.