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. He performed as an understudy in a 1964 Broadway production of Incident at Vichy, and the following year had a supporting role in a Broadway production of Tartuffe. From late 1965 through the spring of 1966, he starred on Broadway as Fray Marcos de Nizza in The Royal Hunt of the Sun.

In 1975, Lo Bianco won an Obie award for his off-Broadway performance as Duke Bronkowski in the baseball-themed play Yanks-3, Detroit-0, Top of the Seventh. In 1983, 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. In 1984, he had a supporting role in the action comedy City Heat, opposite Burt Reynolds and Clint Eastwood.

Lo Bianco first portrayed the larger-than-life 1934–1945 mayor of New York City Fiorello H. La Guardia in the one-man show Hizzoner!, written in 1984 by Paul Shyre. Lo Bianco won a local Daytime Emmy Award for the WNET Public Television version of the play, which was filmed at the Empire State Institute for the Performing Arts in Albany. The play was subsequently staged on Broadway in 1989, where it ran for 12 performances. Lo Bianco appeared in several independent films in the 1990s, and in 1995 appeared as Jimmy Jacobs in the HBO biographical film Tyson, followed by a minor role in Nixon, directed by Oliver Stone.

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 rewritten the play several times, 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. The show was staged at LaGuardia Community College in May 2015.

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.

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.