Totò was born Antonio Clemente on 15 February 1898 in the Rione Sanità, a poor district of Naples, the illegitimate son of Anna Clemente (1881-1947), a Sicilian woman, and the Neapolitan marquis Giuseppe De Curtis (1873-1944). His father did not legally recognize him until 1937. He so regretted growing up without a father that, at age 35, he managed to have the marquis Francesco Maria Gagliardi Focas adopt him in exchange for a life annuity. As a consequence, when Marquis de Curtis recognized him, Totò had become an heir of two noble families, hence claiming an impressive slew of titles.

Totò's mother wanted him to become a priest, but as early as 1913, at the age of 15, he was already acting as a Comedian in small theatres, under the pseudonym Clerment. His early repertoire mostly consisted in imitations of Gustavo De Marco's characters. In the minor venues where he performed, Totò had the chance to meet famous artists like Eduardo and Peppino De Filippo. He served in the army during World War I and then went back to acting. He learned the art of the guitti, the Neapolitan scriptless comedians, heirs to the tradition of the Commedia dell'Arte, and began developing the trademarks of his style, including a puppet-like, disjointed gesticulation, emphasized facial expressions, and an extreme, sometimes surrealistic, sense of humor, largely based on emphasizing primitive urges such as hunger and sexual Desire.

In 1922, he moved to Rome to perform in bigger theatres. He performed in the genre of avanspettacolo, a vaudevillian mixture of music, ballet and comedy preceding the main act (hence its name, which roughly translates as "before show"). He became adept at these shows (also known as rivista – Revue), and in the 1930s he had his own company, with which he travelled across Italy. In 1937, he appeared in his first movie Fermo con le mani, and later starred in 96 other films, many of which still are broadcast frequently on Italian television.

Totò had a reputation as a playboy. One of his lovers, the well known chanteuse and Dancer Liliana Castagnola, committed suicide after their relationship ended. This tragedy marked his life. He buried Liliana in his family's chapel, and named his only daughter Liliana (born 10 May 1933 to his first wife, Diana Bandini Rogliani, whom he married in 1935).

In 1946, when the Consulta Araldica — the body that advised the Kingdom of Italy on matters of nobility—ceased operations, the Tribunal of Naples recognized his numerous titles, so his complete name was changed from Antonio Clemente to Antonio Griffo Focas Flavio Ducas Komnenos Gagliardi de Curtis of Byzantium, His Imperial Highness, Palatine Count, Knight of the Holy Roman Empire, Exarch of Ravenna, Duke of Macedonia and Illyria, Prince of Constantinople, Cilicia, Thessaly, Pontus, Moldavia, Dardania, Peloponnesus, Count of Cyprus and Epirus, Count and Duke of Drivasto and Durazzo. For someone born and raised in one of the poorest Neapolitan neighbourhoods, this must have been quite an achievement, but in claiming the titles (at the time they had become meaningless) the Comedian also mocked them for their intrinsic worthlessness. In fact, when he was not using his stage name Totò, he mostly referred to himself simply as Antonio De Curtis.

During the 1950s, he started to compose poetry. The best-known is probably 'A Livella, in which an arrogant rich man and a humble poor man meet after their deaths and discuss their differences. Totò was also a songwriter: Malafemmena (Wayward Woman), dedicated to his wife Diana after they separated, is considered a classic of the Neapolitan popular music.

As the vast majority of his movies where essentially meant to showcase his performances, many have his name "Totò" in the title. Some of his best-known films are Fifa e Arena, Totò al Giro d'Italia, Totò Sceicco, Guardie e ladri, Totò e le donne, Totò Tarzan, Totò terzo uomo, Totò a colori (the first Italian color movie, 1952, in Ferraniacolor), I soliti ignoti, Totò, Peppino e la malafemmina, La legge è legge. Pierpaolo Pasolini's The Hawks and the Sparrows and the episode "Che cosa sono le nuvole" from Capriccio all'italiana (the latter released after his death), showed his dramatic skills.

Another personal tragedy was the premature birth of his son Massenzio in 1954. The child died a few hours later. He was the son of Totò's mistress Franca Faldini. During a tour in 1956, he lost most of his eyesight due to an eye infection that he had ignored to avoid cancelling his show and disappointing his fans. The handicap however almost never affected his schedule and acting abilities.

Partly because of the radical, naive immorality of his roles, some of his more spicy gags raised much controversy in a society that was both strictly Catholic and ruled by the conservative Democrazia Cristiana (Christian Democracy) party. For Example, Totò's 1960 movie Che fine ha fatto Totò Baby? ("What ever happened to Totò Baby?", a parody of What Ever Happened to Baby Jane?) included a cheeky and gross celebration of cannabis in an era when drugs were perceived by the Italian audience as something as exotic as depraved and dangerous. Nevertheless, such controversies never affected the love of the Italian audience for him.

Totò died at the age of 69 on 15 April 1967 in Rome after a series of heart attacks. Due to overwhelming demand, there were no fewer than three funeral services: the first in Rome, a second in his birth city of Naples—and a few days later, in a third one by the local Camorra boss, an empty casket was carried along the packed streets of the popular Rione Sanità quarter where he was born.