Meredith was born in 1907 in Cleveland, Ohio, the son of Ida Beth (nee Burgess) and Dr. William George Meredith, a Canadian-born physician, of English descent. His mother came from a long line of Methodist revivalists, a religion to which he adhered throughout his lifetime. Meredith graduated from Hoosac School in 1926 and then attended Amherst College (class of 1931). He left Amherst, and became a reporter for the Stamford Advocate.

In 1929, he became a member of Eva Le Gallienne's Civic Repertory Theatre company in New York City. Although best known to the larger world audience for his film and television work, Meredith was an influential actor and director for the stage. He made his Broadway debut as Peter in Le Gallienne's production of Romeo and Juliet (1930) and became a star in Maxwell Anderson's Winterset (1935), which became his film debut the following year. His early life and theatre work were the subject of a New Yorker profile. He garnered critical acclaim in the 1935 Broadway revival of The Barretts of Wimpole Street starring Katharine Cornell. She subsequently cast him in several of her later productions. Other Broadway roles included Van van Dorn in High Tor (1937), Liliom in Liliom (1940), Christy Mahon in The Playboy of the Western World (1946), and Adolphus Cusins Major Barbara (1957). He created the role of Erie Smith in the English-language premiere of Eugene O'Neill's Hughie at the Theater Royal in Bath, England in 1963. He played Hamlet in avant garde theatrical and radio productions of the play. A distinguished theatre director, he won a Tony Award nomination for his 1974 Broadway staging of Ulysses in Nighttown, a theatrical adaptation of the "Nighttown" section of James Joyce's Ulysses. Meredith also shared a Special Tony Award with James Thurber for their collaboration on A Thurber Carnival (1960). In the late seventies, he directed Fionnula Flanagan's one-woman multi-role play "James Joyce's Women," which toured for several years.

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