Melvin Richard Matthews was born in Oakland, California. He initially aspired to become a Roman Catholic priest, studying in San Francisco and then at Gregorian University in Rome in the 1960s. However, his growing interest in drama led him to the Juilliard School, where he taught, among others, Kevin Kline and Patti LuPone.

He began his stage career in 1965 in the San Francisco Bay Area, appearing in both the Marin and California Shakespeare Festivals, eventually becoming a member of the acting ensemble of the American Conservatory Theatre. In the late 1980s, settling permanently in Los Angeles, Matthews began guest-starring in television series and appearing in films. He starred in series such as Down Home, Soul Man and, most successfully, The Jeff Foxworthy Show.

In 1989 he starred in the preshow for EPCOT Center's Body Wars attraction in The Wonders Of Life Pavilion. He also has made many guest appearances on television, including Remington Steele, Dallas, Murder She Wrote, L.A. Law, The Nanny, True Blood, Just Shoot Me!, Star Trek: Voyager, The West Wing, Gilmore Girls (as Headmaster Charleston), Ally McBeal, Coach, The Practice, Who's the Boss?, Charmed, The King of Queens (as Doug Heffernan's father Joe), NYPD Blue, Desperate Housewives (appearing in every Season except 5 as Reverend Sykes), House M.D. (appearing in 2004 in "Damned If You Do" the 5th episode of the 1st season playing the role of Marvin/Santa Claus), Blue Bloods (as of 2016 appearing in "Help Me Help You" the 16th episode of the 6th season playing the role of Judge Wilson), Two and a Half Men and Carnivàle.

Matthews was also Artistic Director of the Berkeley Shakespeare Festival, the California Actors Theatre, The Antaeus Theatre Company (which he co-founded in 1991), and the Andak Stage Company; he is an Associate Artist of the Old Globe Theatre; and a founding member of the John Houseman's The Acting Company and Sam Mendes' Bridge Project.

He is also a Playwright, Director, and theater scholar who has published books and articles on Shakespeare and translations of 17th-century Spanish theater. He has been a dramaturg on numerous theatrical productions, including the 2005 Broadway revival of Julius Caesar starring Denzel Washington and the 2003 revival of Henry IV, winning a Drama Desk Award Special Award for his adaptation of the latter.

Matthews appeared in the 2009 world tour of The Bridge Project as "Pishchick" in The Cherry Orchard and "Antigonus" in The Winter's Tale. In the 2011 summer season of The Public Theater's Shakespeare in the Park, he performed as "the Provost" in Measure for Measure and "Lafew" in All's Well That Ends Well. and as "Sir Humphrey" in the American premiere of Yes Prime Minister at the Kirk Douglas Theatre. He was nominated for an Ovation Award for Book and Lyrics of an original musical entitled Liberty Inn, which he co-wrote with B. T. Ryback.

In 2010, Matthews joined the cast of the ABC soap opera General Hospital as Judge Peter Carroll, the judge in Sonny Corinthos' trial.

In 2011, his verse translation of The Capulets & The Montagues played at the Andak Stage Company and the International Siglo de Oro Festival, winning the L.A. Drama Critics Circle Award for Best Adaptation. Matthews appeared twice as Santa Claus in The Big Bang Theory Season 6 episode, "The Santa Simulation" and Season 8 episode "The Clean Room Infiltration".

He was the dramaturg for the Lincoln Center production of Macbeth (2013), directed by Jack O'Brien and starring Ethan Hawke. He appeared as "Richard Russell" in Robert Schenkkan's award-winning L.B.J. play All The Way, starring Bryan Cranston, at A.R.T. in Cambridge in September 2013.

He appeared as "Mickey Goldmill" in the Broadway musical Rocky the Musical in 2014, then in 2015, he went on to play Winston Churchill opposite Helen Mirren as Queen Elizabeth II in Peter Morgan's The Audience on Broadway. Matthews portrayed Judge Byers in the 2015 film Bridge of Spies. He portrayed "Joe" in the new musical Waitress that opened on Broadway in April 2016.