His great passion for music showed up at a very young age. When he was 11, his parents enrolled him at the Giuseppe Verdi Conservatory in Turin. During his teen years, he performed in his hometown's night clubs as jazz singer or playing double bass and violin.

During World War II, he ended up in a US internment camp in Sardinia. Some military understood his musical talent, and had him join the orchestra of the allied radio station of Cagliari. This enabled Buscaglione to continue to make music in those war years, and to experiment with new sounds and rhythms coming from the US. Most foreign music had been officially forbidden by the Italian Fascist regime.

After the war, Buscaglione returned to Turin and resumed working as a musician for various bands. He then formed his own group, the Asternovas. In the meantime he was gradually creating his public character, inspired by Clark Gable and Mickey Spillane's gangsters. His friend Leo Chiosso, a lyricist who formed a very good songwriting duo with Buscaglione, provided him with humorous stories about gangsters and their babes, New York and Chicago, tough men who were ruthless with enemies but easily fell victims to a woman's charms. They wrote together the hits that brought nation-wide fame to Buscaglione: Che bambola, Teresa non sparare, Eri piccola così, Guarda che luna, Love in Portofino, Porfirio Villarosa, Whisky facile.

By the end of 1950s, Buscaglione was one of Italy's most demanded entertainers, not just singers. He appeared on advertising campaigns, on television, in movies, where he always played his amiable braggart role.

Buscaglione died unexpectedly at only 39 years old. He was killed in a car accident, his pink Ford Thunderbird crashing against a truck at the first light of dawn.