Pendleton was born in Warren, Ohio, the son of Thorn Pendleton, who ran a tool company, and Frances Manchester Pendleton, a professional actress. Pendleton is a graduate of Yale University, School of Drama.
Pendleton first received critical acclaim in 1964 for his performance as Motel in the original Broadway cast of Fiddler on the Roof. He appeared in The Last Sweet Days of Isaac (for which he won the Drama Desk Award for Outstanding Performance and an Obie Award), The Diary of Anne Frank, Goodtime Charley, and Up from Paradise as well as many other plays. In August 2006, Pendleton played the Chaplain in Bertolt Brecht's Mother Courage and Her Children with Meryl Streep and Kevin Kline in the New York Shakespeare Festival/Public Theater production directed by George C. Wolfe at the Delacorte Theater in Central Park, New York City. In 2007, he appeared as Friar Lawrence in the Public Theater's production of Shakespeare's Romeo and Juliet at the Delacorte Theater.
Pendleton wrote the plays Uncle Bob, Booth, and Orson's Shadow, all of which were staged off-Broadway.
As a director, Pendleton has worked extensively on and off-Broadway. His direction of Elizabeth Taylor and Maureen Stapleton in Lillian Hellman's The Little Foxes garnered him a Tony Award nomination in 1981. Additional directing credits include The Runner Stumbles by Milan Stitt (1977), Spoils of War by Michael Weller (1988), and The Size of the World by Charles Evered (1996).
Pendleton is also a member of The Mirror Theater Ltd's Mirror Repertory Company, directing the company’s 1984 production of Henrik Ibsen’s Ghosts, starring Geraldine Page, Sabra Jones, and Victor Slezak. His play H6R3, a compilation of Henry 6 and Richard 3 together in order to make the storyline clearer and strengthen the women’s parts, became a benefit production of The Mirror Theater Ltd at the then Promenade Theater in New York. Pendleton played Richard in this performance, Sabra Jones performed Elizabeth, Lynn Redgrave played Mad Margaret, Charles McAteer was Lord Rutland, Geraint Wyn Davies played Henry V1, Daniel Gerroll played Buckingham, and Lisa Pelikan played Lady Anne.
In 2009 Pendleton directed Uncle Vanya, starring Maggie Gyllenhaal and Peter Sarsgaard, at the Classic Stage Company. The same year he directed Tennessee Williams' autobiographical play Vieux Carré at The Pearl Theatre Company. In January and February 2010, Pendleton directed two plays, Bus Stop at The Olney Theatre and Golden Age at the Philadelphia Theatre Company. His 2011 directing of Three Sisters won him an Obie Award. In 2012 he directed a production of Detroit at the National Theatre in London, England.
Pendleton served as Artistic Director for Circle Repertory Company with associate artistic director Lynne Thigpen. The Company closed in 1996.
He currently teaches acting at the HB Studio and directing at The New School, both in Greenwich Village. Pendleton has been involved with the Steppenwolf Theatre in Chicago since directing Ralph Pape's Say Goodnight, Gracie for the 1979-80 season, and is currently an ensemble member there. His acting credits at Steppenwolf include Uncle Vanya, Valparaiso, and Educating Rita.