Lo Bianco first portrayed the larger-than-life 1934-1945 mayor of New York City Fiorello H. LaGuardia in a one-man show, Hizzoner!, written in 1984 by Paul Shyre. The play closed in 1989 after 12 Broadway performances.

Lo Bianco was born in Brooklyn, New York, the son of a housewife mother and a taxi driver father. He is known for his tough guy roles in the cult films The Honeymoon Killers, God Told Me To, and The French Connection. Lo Bianco was a Golden Gloves boxer and also founded the Triangle Theatre in 1963, serving as its artistic Director for six years and collaborating with lighting designer Jules Fisher, Playwright Jason Miller and actor Roy Scheider. Lo Bianco won an off-Broadway Obie award for Yanks-3, Detroit-0, Top of the Seventh. Most notably, Lo Bianco was nominated for a Tony for his portrayal of Eddie Carbone in Arthur Miller's A View from the Bridge. He also won the 1983 Outer Critics Circle Award for this performance.

Lo Bianco was married from 1964 until 1984 to Dora Landey. They had three daughters. He was married to Elizabeth Fitzpatrick from 2002 until 2008. He married his current wife, Alyse Best Muldoon, in June 2015.

Lo Bianco, an Italian American, was the National Spokesperson for the Order Sons of Italy in America. His humanitarian efforts have earned multiple awards, including Man of the Year for Outstanding Contributions to the Italian-American Community from the Police Society of New Jersey; a Man of the Year Award from the State of New Jersey Senate; a Lifetime Entertainment Award from the Columbus Day Parade Committee; the 1997 Golden Lion Award; Humanitarian Award of the Boys' Town of Italy.

Lo Bianco continued his work on the life of LaGuardia in a revised revival of the play in 2008, titled LaGuardia. His third incantation of the mayor's life that had a limited run off Broadway in October 2012, titled The Little Flower. Lo Bianco has been constantly rewriting the play, which he purchased from Shyre's estate, and he views it as "a vehicle to express my concerns for the public and the political mess that we're in, which we continue to be in I think, and try to relate answers to failure." He performed it in Moscow shortly before the fall of the Soviet Union, and in 2015 was scheduled to perform it in Italy.

Lo Bianco tends to be politically conservative, though he distrusts political labeling as "too simplistic" and "an escape from responsibility". In October 2014, he opposed the Metropolitan Opera's decision to stage the controversial play The Death of Klinghoffer, which he described as "outrageous" because it "tries to justify the killing of a helpless man in a wheelchair because he happens to be Jewish".

A New York Times profile in 2015 reported that Lo Bianco was at work on a one-man show playing himself and a film script about his early life.