The son of working-class Lithuanian Jewish immigrants, Simon discovered a love of theatre while working under director Joan Littlewood in London in the 1950s. Returning to Johannesburg, he supported himself as an advertising copywriter while producing and directing plays. Before he opened the Market, he staged multi-racial plays anywhere he could: in warehouses and shantytowns, storefronts and back yards, including Fugard's The Blood Knot (1961). Simon spent a year (1969-70) in New York, where he introduced South African plays to an American audience and edited the journal New American Review.

Barney Simon co-founded Johannesburg’s Market Theatre in 1976. The Market Theatre was South Africa's first multiracial cultural center and a birthplace of the country’s indigenous theater movement. Working under the racial segregation laws of apartheid without state subsidies and under constant threat of arrest for staging controversial contemporary plays performed by multiracial casts in front of multiracial audiences, Simon remained the theater’s artistic director from its opening until he died. He was the first to stage many of Athol Fugard’s plays, directed a film for the BBC of Nadine Gordimer’s story City Lovers, and worked with screen writer Jean-Claude Carrière on the French translation for the Paris production by Peter Brook of Simon’s last play, The Suit (Le Costume) (1994).

Simon was known for his method of creating and developing original plays through a workshop process of field research, improvisation and collaborative writing, sometimes with untrained actors or combinations of musicians, professional actors and people entirely new to the theater.

Simon was active in South African literature as the editor of The Classic from 1964-1971, the influential South African journal of township literature founded by Nathaniel Ndazana Nakasa in 1963. Simon edited an autobiographical novel by Dugmore Boetie, Familiarity is the Kingdom of the Lost, for which Simon also wrote an afterword. He also published a collection of his own stories, Jo'berg Sis, in 1974.

Partial list of plays by Simon

• Phiri (1972)
• Hey Listen (1973)
• People (1973)
• People Too (1974)
• Storytime (1975)
• Cincinnati (1979)
• Cold Stone Jug (1980)
• Call Me Woman (1980)
• Marico Moonshine and Manpower (1981)
• WOZA ALBERT! (1981)
• Black Dog-Inj Mayama (1984)
• Born in the RSA (1985)
• Outers (1985)
• Klaaglied vir Kous (1986)
• Written by Hand (1987)
• Inyanga - about Women in Africa (1989)
• Eden and Other Places (1989)
• Score me the Ages (1989)
• Starbrites (1990)
• Singing The Times (1992)
• Silent Movie (1993)
• The Suit (1994)