Among his most successful works were The Cradle Will Rock, whose premiere was directed by Orson Welles, the opera Regina, an adaptation of Lillian Hellman The Little Foxes, and his Broadway adaptation of Bertolt Brecht and Kurt Weill's ''Threepenny Opera.
The dramatic premiere of the pro-union The Cradle Will Rock was at the Venice Theater on June 16, 1937. The cast had been locked out of the WPA Theater by government troops, and so an impromptu performance without sets or costumes took place, with actors and musicians performing from the audience and Blitzstein narrating at the piano. The 1999 Tim Robbins directed movie Cradle Will Rock features this event, although somewhat fictionalized.
In 1939, Blitzstein's close friend Leonard Bernstein led a revival of the play at Harvard, narrating from the piano just as Blitzstein had done.
In 1958 he was subpoenaed to appear before the House Committee on Un-American Activities. In closed session he admitted having been a member of the Communist Party and then refused to "name names", and wound up not being called upon to testify publicly.