[1] Typically playing losers, marginalised, working-class characters yet "in possession of their dignity, morality, and underlying optimism",[2] he was referred to as "one of the few truly complete actors in Italian cinema".

[3] His father recruited in Public Safety, where he reached the rank of Maresciallo, and in the early 1930s, he was transferred to Rome, where Nino and his younger brother Dante spent their childhood in the popular neighborhood of San Giovanni.

[3][5] To please his family in October 1941, he enrolled at the university in the Faculty of Law, but already in the same year he showed an interest and a natural inclination for the stage, making his debut as a presenter and an actor in the theater of a parish in Rome.

[3] After 8 September 1943, in order to avoid conscription, he took refuge for a year with his brother in the mountains above Cassino;[3] returned to Rome in 1944, he resumed his university studies and, at the same time, he enrolled at the National Academy of Dramatic Art.

[3] In 1948, he entered the company of the Piccolo Teatro di Milano under Giorgio Strehler, playing in tragedies such as Romeo and Juliet and The Storm.

[3] In 1959, the trio was chosen by RAI to host Canzonissima; the show marked the turning point of the career of Manfredi, who enjoyed a very large popularity, mainly thanks to the "macchietta" (i.e. comic caricature) of the "Barman from Ceccano".

[6] Starting from the second half of the 1960s, Manfredi became a top actor at the Italian box office, starring in some of the most successful and critically acclaimed films in the Commedia all'italiana genre, often directed by Dino Risi.

[3][9] In the 1970s and early 1980s, he continued alternating high-profile works and less ambitious comedies; among the most successful performances of the time, the emarginated immigrant of Bread and Chocolate (1973), the idealist worker of We All Loved Each Other So Much (1974), the old shanty town patriarch of Down and Dirty (1976), the Vatican's magistrate of In the Name of the Pope King (1977), the abusive coffee-seller in Café Express (1980).

[3] In 1983, he debuted as author with the book Proverbi e altre cose romanesche, while in 1984, he signed his first work as playwright and stage director (Viva gli sposi), an activity in which he gradually focused.

[11] Starting from Un commissario a Roma his popularity revamped thanks to a series of successful RAI TV-series and miniseries, notably Linda e il brigadiere.

From an early age, Manfredi suffered from a biliary disorder which forced him to a very strict diet, and his meals often consisted of just light tea or caffè d'orzo.