McClure's first book of poetry, Passage, was published in 1956 by small press publisher Jonathan Williams. His poetry is heavily infused with an awareness of nature, especially in the animal consciousness that often lies dormant in mankind. Not only an awareness of nature, but the poems are organized in an organic fashion, continuing with his appreciation of nature's purity. Stan Brakhage, friend of McClure, stated in Chicago Review that:

"McClure always, and more and more as he growsolder, gives his reader access to the verbal impulses of his whole body'sthought (as distinct from simply and only brain-think, as it is withmost who write). He invents a form for the cellular messages of his,a form which will feel as if it were organic on the page; and he stickswith it across his life..."

McClure has since published eight books of plays and four collections of essays, including essays on Bob Dylan and the environment. His fourteen books of poetry include Jaguar Skies, Dark Brown, Huge Dreams, Rebel Lions, Rain Mirror and Plum Stones. McClure famously read selections of his Ghost Tantra poetry series to the caged lions in the San Francisco Zoo. His work as a novelist includes the autobiographical The Mad Cub and The Adept.

On January 14, 1967, McClure read at the epochal Human Be-In event in Golden Gate Park in San Francisco and transcended his Beat label to become an important member of the 1960s Hippie counterculture. Barry Miles famously referred to McClure as "the Prince of the San Francisco Scene".

McClure would later court controversy as a playwright with his play The Beard. The play tells of a fictional encounter in the blue velvet of eternity between Billy the Kid and Jean Harlow and is a theatrical exploration of his "Meat Politics" theory, in which all human beings are "bags of meat."

Other plays include Josephine The Mouse Singer and VKTMS. He had an eleven-year run as playwright-in-residence with San Francisco's Magic Theatre where his operetta "Minnie Mouse and the Tap-Dancing Buddha" had an extended run. He has made two television documentaries — The Maze and September Blackberries — and is featured in several films including The Last Waltz (dir. Martin Scorsese) where he reads from The Canterbury Tales; Beyond the Law (dir. Norman Mailer); and, most prominently, The Hired Hand (dir. Peter Fonda).

McClure was a close friend of The Doors lead singer Jim Morrison and is generally acknowledged as having been responsible for promoting Morrison as a poet. To this day, McClure still performs spoken word poetry concerts with Doors keyboard player Ray Manzarek and they have released several CDs of their work. McClure is the author of the Afterword in Danny Sugerman's seminal Doors biography, No One Here Gets Out Alive. McClure has also released CDs of his work with minimalist composer Terry Riley. McClure’s songs include "Mercedes Benz," popularized by Janis Joplin, and new songs which are being performed by Riders on the Storm, a band that consists of original Doors members Ray Manzarek and Robbie Krieger.

McClure's journalism has been featured in Rolling Stone, Vanity Fair, The L.A. Times and The San Francisco Chronicle. He has received numerous awards, including a Guggenheim Fellowship, an Obie Award for Best Play, an NEA grant, the Alfred Jarry Award and a Rockefeller grant for playwriting. McClure is still active as a poet, essayist and playwright and lives with his second wife, Amy, in the San Francisco Bay Area. He has one daughter from his first marriage to Joanna McClure.

McClure's play The Beard debuted at the Actor’s Workshop Theatre in San Francisco on the December 18, 1965. A second performance followed at Bill Graham’s Fillmore Auditorium on the July 24, 1966. With the Fillmore’s high profile, the play attracted an audience of 700. After success at the Fillmore, the following month the play opened at The Committee, a theatre nightclub in the North Beach area of the city, where it was hoped it would enjoy a lengthy run.

Now aware of the play’s subject matter, the San Francisco Police Department secretly tape-recorded the first two performances and secretly filmed the third performance. Having failed in their attempts to successfully censor Allen Ginsberg’s Howl, the performances of Lenny Bruce and the San Francisco Mime Troupe, the police department was intent to succeed this time.

At the end of that third performance on August 8, 1966--only the fifth time the play had been performed in public--the SFPD raided the venue and arrested actors Billie Dixon (Jean) and Richard Bright (Billy). Under Penal Code Section 647(a) the pair were initially charged with “obscenity”, then “conspiracy to commit a felony” and ultimately with “lewd or dissolute conduct in a public place.”

The American Civil Liberties Union took the case and represented the actors. Twelve days after the arrests, the play was performed at The Florence Schwimley Little Theatre, in Berkeley. The audience included more than a hundred ACLU-invited expert witnesses, including political activists, academics, writers and even members of the clergy. Seven members of the Berkeley Police Department and the District Attorney’s office were also present. Five days later, the city of Berkeley brought its own charges of “lewd or dissolute conduct” against the play. It became a theatrical cause célèbre, until finally, after months of legal deliberation, Judge Joseph Karesh of the San Francisco Superior Court ruled that while the play did contain material of a troublesome nature, it was not appropriate to prosecute such work under the law. All the charges were dropped and the subsequent appeal lost.

Unable to perform in the San Francisco area, the play moved to Los Angeles where the play's attempt at a run was disrupted by the arrest of both Dixon and Bright at curtain down of fourteen consecutive performances. McClure recalls, “The actor and the actress actually got two standing ovations, one at the end of the play and the second when the police hauled them out of the door and into the waiting wagon and took them off to book them.”

The Beard eventually transferred to New York where in the 1967—1968 Obie Theatre Awards, it won Best Director and Best Actress. It has since played successfully all over the world and is a favorite with American university drama groups. It is interesting to note that the play has enjoyed particular success in London, having been performed there twice. In 1968, actor Rip Torn directed a notable production at The Royal Court Theatre and it has most recently been revived at a smaller venue, the Old Red Lion Theatre in 2006 under the direction of Nic Saunders with new music by Terry Riley. The play is currently out of print in both the US and UK. Saunders would collaborate with McClure a second time in 2008 on the award-winning short film Curses and Sermons which would mark the first time McClure had authorised a filmed adaptation of one of his poems.