Born in Rome, before World War II Lizzani worked as a scenarist on such films of as Roberto Rossellini's Germany Year Zero, Alberto Lattuada's The Mill on the Po (both 1948) and Giuseppe De Santis' Bitter Rice (1949), for which he received an Academy Award nomination for Best Original Story.
After directing documentaries, he debuted as a feature director with the admired World War II drama Achtung! Banditi! (1951). Respected for his awarded drama Chronicle of Poor Lovers (1954), he has proven a solid director of genre films, notably crime films such as The Violent Four (1968) and Crazy Joe (1974) or crime-comedy Roma Bene (1971). His film L'oro di Roma (1961) examined events around the final deportation of the Jews of Rome and the Roman roundup, grande razzia, of October 1943. For his 1968 film Bandits in Milan he won a David di Donatello award as best director and a Nastro d'Argento award for best screenplay.
Lizzani worked frequently for Italian television in the 1980s and supervised the Venice International Film Festival for four editions, from 1979 to 1982. In 1994 Lizzani was a member of the jury at the Berlin Film Festival.
For his 1996 film Celluloide, which deals with the making of Rome, Open City, he received another David di Donatello award for his screenplay.