After secondary school, Troisi wrote some poems inspired by his favourite author, Pier Paolo Pasolini, and, in 1969, started to play in a small local theatre together with some childhood friends (including Lello Arena and Enzo Decaro).

The early death of his mother condemned Troisi to a harsh period of activity, which is said to have had a role in the development of his increasingly serious heart problems which were brought on during his teenage years from bouts of rheumatic fever.

They gained national fame on the radio and increased it consistently from 1977 onwards eventually becoming TV stars with the shows Non Stop, La sberla (1978) and Luna Park (1979).

He was noted for his use of facial mimicry and of apparently confused speech—in these he drew inspiration from such famous figures of Neapolitan comedy as Totò, and Eduardo and Peppino De Filippo.

Like his second film, Ricomincio da tre is centered on the troublesome love life of a Neapolitan character, partly inspired by Troisi's youth, as well as featuring Lello Arena.

Troisi starred opposite Roberto Benigni in Non ci resta che piangere (1984), in which they play two friends who are accidentally transported back in time to the 15th century; there they meet Leonardo da Vinci and, upon realising which age they are in, travel to Spain to try to stop Christopher Columbus from discovering the Americas.

His last film as director (also as screenwriter and actor) was Pensavo fosse amore, invece era un calesse (1991), again centering on the everyday difficulties of love between a man and a woman (portrayed by Francesca Neri).