In October 1957 he became an assistant stage manager, theatre Painter and general dogsbody to John Bury, the theatre designer, and he went on stage in his first professional role as the Queen's Messenger in the then in rehearsal production of Macbeth. From the Scottish Court to a building site his next performance was as a bricklayer in You Won't Always Be On Top, soon followed by a peasant in And the Wind Blew, Bellie in Pirandello's Man Beast and Virtue, Calisto in De Rojas's Celestina; Young Jodi Maynard in Paul Green's Unto Such Glory (all 1957) and then came the last play of the 1957-58 season which was to be the start of an extraordinary year in the history of theatre workshop and Melvin's career. He was cast as Geoffrey in Shelagh Delaney's play, A Taste of Honey. After the summer break in 1958, he played the title role in the seminal production of Brendan Behan's The Hostage. Both scripts had been transformed in rehearsals by Joan Littlewood's painstaking and inspired methods of getting to the truth of the text and building a lively poetic and dangerous theatrical event. Though both plays were to blow a refreshing wind through the British theatre, neither play transferred to the West End immediately, so Melvin stayed on to play Scrooge's nephew in Joan Littlewood's adaptation of A Christmas Carol (1958).

In February 1959, A Taste of Honey opened at the Wyndham's Theatre and transferred to the Criterion some six months later. It was the hit of the season. Melvin went on to play his role of Geoffrey in the film of A Taste of Honey, directed by Tony Richardson, for which he won the Prix de Cannes as best actor at the festival in 1962. He was also nominated for the BAFTA "Most Promising Newcomer" award.

He appeared in the very first episode of the cult television series The Avengers in 1960.

The production attracted the interest of filmmakers, including Ken Russell and Lewis Gilbert. Melvin became a member of what has often been called the Ken Russell Repertory Company, appearing in many of Russell's most celebrated films, including The Devils and The Boy Friend. Lewis Gilbert cast Melvin in H.M.S. Defiant (1962), alongside Dirk Bogarde, and in Alfie, where he played Michael Caine's work friend, stealing petrol and taking photographs to sell to tourists.

The production of Oh, What a Lovely War! in New York in 1964 was his last for Joan Littlewood and the Theatre Workshop Company.

Several commercial available audio recordings have been made featuring Murray Melvin. These include four plays on LPs produced by Caedmon Records (Two Gentlemen of Verona (1965); A Midsummer's Night Dream; Bernard Shaw's St. Joan (1966); The Poetry of Kipling). His performance in Oh, What a Lovely War is available on Decca Records (1969).

He played the Dauphin in Shaw's St. Joan, directed in 1966 by Waris Hussein. He played Bertold in a television production of Pirandello's Henry IV directed by Michael Hayes; Don Pietro in Peter Drummond's film of The Little World of Don Camillo; and The Hermit in Mai Zetterling's production of William Tell. He also appeared as the Barber in Rex Harrison's Don Quixote in the 1973 television film directed by Alvin Rakoff.

He appeared in the swinging sixties comedy Smashing Time (1967), which also featured Bruce Lacey and his robots. Ken Russell had made a film about Lacey called The Preservation Man (1962).

He starred in The Tyrant King, the six-part children's television series directed in 1968 by Mike Hodges. In 1973 he played a crucial role in the last two episodes of The Flaxton Boys, where he plays the upper-class twit character Gerald Meder.

In Russell's The Boy Friend (1971), Melvin and another Theatre Workshop regular, Brian Murphy, are among the company players trying to catch the eye of a Hollywood Producer who watches their provincial performance of Sandy Wilson's The Boy Friend. In the film, Melvin has a spectacular solo dance number in a caped French officer's outfit.

Peter Medak cast Melvin in five films: A Day in the Death of Joe Egg (1972), starring Alan Bates; Ghost in the Noonday Sun (1973, starring Peter Sellers); The Krays (1990); Let Him Have It (1991); and as Dr. Chilip in David Copperfield (2000).

He had an important role as Reverend Samuel Runt in Stanley Kubrick's Barry Lyndon (1975). In the video project "Stanley and Us", Melvin talks about Kubrick's "57 takes (plus 20)".

He co starred with Russell regular Oliver Reed in Richard Fleischer's film of The Prince and the Pauper Crossed Swords (1977) and in Alberto Lattuada's four part television film Christopher Columbus (1985).

He appeared in Russell's film about the poet, Samuel Coleridge, The Rime of the Ancient Mariner (1978).

He has featured in two films by Christine Edzard, Little Dorrit (1988), and As You Like It (1992).

In 1991, thirty four years after first making the tea and sweeping the stage at the Theatre Royal, he was invited to become a member of the board of the theatre, a position he held until 2011. It is partly in this role that he is becoming widely known as a learned and popular theatre and film Historian — he can be seen and heard, for Example, on the BFI DVD release of the Bill Douglas Trilogy.

In 1992 he became the Theatre Royal's voluntary archivist and in 2009 he was appointed a member of the Theatre Workshop Trust. He led the successful campaign to erect a statue of Joan Littlewood in Theatre Square at Stratford.

In 1994, Melvin supplied the voice of the villain Lucius on the British children's animated TV series Oscar's Orchestra for the BBC and France 3.

In 1998 he appeared in a Christmas Special episode of the BBC's Jonathan Creek called "The Black Canary".

In 2004 he appeared as Monsieur Reyer, the musical Director and Conductor of the Opera Populaire, in Joel Schumacher's film adaptation of the musical The Phantom of the Opera.

In 2007, he narrated Tales of the Supernatural Volume 3 by M. R. James for Fantom Films. This was followed in 2009 by M.R. James - A Ghost Story for Christmas, and in 2011 and 2012 by two recordings of Wilkie Collins: Supernatural Stories, Volumes 2 & 3 and The Dark Shadows Legend :The Happier Dead.

In July 2011 Melvin played the Professor in a short comedy/drama called The Grey Mile, a story about two ex master Criminals who are now confined to a care home.

On 18 July 2013, he was awarded an honorary degree of Doctor of Arts by De Montfort University and in July 2015 he was awarded an honorary degree by the University of Essex.