From his earliest years, Gruenberg played both solo recitals and in ensembles and in his early twenties he went to study in Europe with the great pianist and composer, Ferruccio Busoni, at the Vienna Conservatory.
Perhaps the high point of his public career came in 1933-34 when the Metropolitan Opera produced his expressionistic opera, The Emperor Jones, based on the play by Eugene O'Neill, with Lawrence Tibbett in the leading role. It was performed by the Met eleven times in two seasons, was featured on the cover of "Time" Magazine and received great critical acclaim.
In 1944 Jascha Heifetz commissioned and premiered the Violin Concerto, Op. 47 with Eugene Ormandy and The Philadelphia Orchestra. The work was also recorded with Pierre Monteux and the San Francisco Symphony Orchestra. During the last two decades of his life, Gruenberg maintained a close friendship with Arnold Schoenberg until the latter's death in 1951, and was elected a member of the National Institute of Arts and Letters. He continued to compose until his death in 1964 and the output of his later years is formidable. Among many other works he composed five symphonies, four full length operas (Volpone, The Emperor Jones, Jack and the Beanstalk and Antony and Cleopatra) and a lengthy oratorio entitled A Song of Faith.