Welch was born in Phoenix, Arizona, but moved with his mother and sister to California in 1929. He enlisted in the Army Air Corps in 1944 but never saw active service. He worked for a period before joining Stockton Junior College, where he developed an interest in the works of Gertrude Stein.

In 1948, Welch moved to Portland, Oregon to attend Reed College. There he roomed with poets Gary Snyder and Philip Whalen. Welch decided to become a writer after reading Gertrude Stein's long story "Melanctha." Welch wrote his thesis on Stein and published poems in student magazines. William Carlos Williams visited the college and met the three poets. He admired Welch's early poems and tried to get his Stein thesis published.

After college, Welch moved to New York City, where he worked writing copy in the advertising industry. Welch was said to have come up with the advertising slogan ,"Raid Kills Bugs Dead", but others have questioned this claim.. In any case, it's doubtful Welch would want to be remembered for it. During this time, Welch started to display emotional and mental problems and went to Florida to take a course of therapy.

He then went to the University of Chicago, where he studied philosophy and English. In Chicago, he joined the advertising department of Montgomery Ward. He was working there at the time of the famous poetry reading at the Six Gallery in San Francisco that launched what was to become known as the San Francisco Renaissance.

Wanting to get back to poetry, Welch applied for a transfer to Montgomery Ward's Oakland headquarters. After the return to California, he started to get involved in the San Francisco literary scene. He soon gave up advertising and earned a living driving a cab while devoting more time to writing. He became an active participant in Beat culture, living at various times with Snyder and Lawrence Ferlinghetti. In 1960, poet Lenore Kandel met Welch and Snyder, who introduced her to many people in the Beat movement.

Jack Kerouac based his character Dave Wain in his novel Big Sur (1962) on Welch.

He had a common-law relationship with Polish refugee Magda Cregg. He acted as the stepfather of her son Hugh Anthony Cregg, III. Cregg later chose the stage-name Huey Lewis in honor of Welch.

On May 23, 1971, he walked out of poet Gary Snyder's house in the mountains of California, leaving behind a suicide note. He had carried his 303-30 rifle. His body was never found.

Note: Before committing suicide in 1971, Lew Welch left a note naming Donald Allen his literary executor. Donald Allen published much of Welch's work posthumously via Grey Fox Press.

• Trip Trap: Haiku on the Road (1973) (ISBN 0912516046) Jack Kerouac, Albert Saijo, and Lew Welch
• How I Work as a Poet (1973) (ISBN 0-912516-06-2)
• Selected Poems, with a preface by Gary Snyder (1976) (ISBN 0-912516-20-8)
• On Bread and Poetry: A Panel Discussion Between Gary Snyder, Lew Welch, and Philip Whalen (1977) (ISBN 0-912516-27-5)
• I, Leo: An Unfinished Novel (1977) (ISBN 0-912516-24-0)
• Ring of Bone: Collected Poems (1979) (ISBN 0-912516-03-8)
• I Remain - The Letters of Lew Welch & the Correspondence of His Friends (Volume 1: 1949-1960) (1980) (ISBN 0-912516-08-9)
• I Remain - The Letters of Lew Welch & the Correspondence of His Friends (Volume 2: 1960-1971) (1980) (ISBN 0-912516-42-9)
• How I Read Gertrude Stein (1995, originally written late-1940's) (ISBN 0-912516-23-2)

Aram Saroyan; Genesis Angels- The saga of Lew Welch & the Beat Generation. William Morrow & Co New York 1979