William Humphrey was born on June 18, 1924, in Clarksville, Texas, to Clarence and Nell (Varley) Humphrey. Located in Red River County in Northeast Texas, Clarksville was more a part of the old South than the Texas West. It was a community built around cotton farming and provided the setting for many of Humphrey's short stories and novels. He spent his early years with his parents in and around Clarksville, moving from one rented house to another--15 in one five-year period. His father, an auto mechanic, was described by Humphrey's own account as a quick-tempered, self-destructive son of an Indian and brother of a bank robber. An expert hunter who lived fast, drove fast, and drank more as the Depression deepened, his death in an auto accident when Humphrey was thirteen forced William and his mother to leave Clarksville and move to Dallas to live with relatives.

Humphrey excelled in school from an early age and after moving to Dallas was able to attend an art academy on scholarship. He attempted to join the Navy during World War II, but was rejected for being color blind. He soon dropped the idea of becoming an artist and began to focus on writing. He attended the University of Texas and Southern Methodist University in the early 1940s, but in 1944 he left SMU in his final semester and headed for Chicago, working various odd jobs. He later moved to Greenwich Village in New York where he met a painter named Dorothy (Feinman) Cantine. She left her husband and married Humphrey in 1949.

That same year, Humphrey began teaching writing and English at Bard College and published his first short story, in . Fellow Texan Katherine Anne Porter had helped Humphrey get started as a writer and came to Bard as a lecturer at his invitation. The two remained close for years, but suffered a falling out in the early 1970s over his role in the publication of . While at Bard, Humphrey also formed a close relationship with poet Theodore Weiss. These two became great supporters of each other's work and corresponded often in later years, relaying thoughts and suggestions on their latest pieces.

Humphrey soon published additional stories in , , , and other magazines. These were eventually published in collected form in his first book (1953). These stories reflect Humphrey's life in 1930s Clarksville and are filled with characters and events based on his family and friends from that time.

Humphrey's first novel, (1957), continued to draw on his Clarksville experiences. Although at first Humphrey was labeled a "western" writer due to the color and humor of his writing and his Texas roots, showed his grounding in the Southern writing tradition, more akin to Faulkner in his use of dialog and his treatment of time, family, and place.

The success of the novel (made into a motion picture in 1960) allowed Humphrey and his wife to travel extensively and pursue his passion for fly fishing. They moved to England in 1958 and later lived in Italy. While in England, Humphrey met publisher Ian Parsons with whom he had corresponded for years. Parsons' firm, Chatto & Windus, published most of Humphrey's books in the UK and the two forged a lifelong friendship during Humphrey's stay.

While in Europe, Humphrey continued to publish stories in major magazines such as and , and in 1963 returned to the U.S. for a one-year appointment as a lecturer at Washington and Lee University in Virginia. In 1965 he took a one-year position at MIT and bought an apple farm in Hudson, New York. Although he would still travel extensively in the coming years, and took other short term positions at Smith College (1976) and Princeton (1981), Hudson remained his home for the rest of his life.

Humphrey's second novel (1965) again combined elements of Western comedy and Southern tragedy in a story of four generations of the Ordway family and their movement west after the Civil War. The book received strong critical reviews and was followed with equal acclaim by his second collection of short stories, (1968). Most of the stories were written while he was living in Italy and working on . Once more the focus was on the Northeast Texas of his youth, and with its themes of poverty, desperation, and prejudice during the 1930s, the book related well to the social concerns of the late 1960s.

Many of Humphrey's works reflected his love and knowledge of the outdoors, and in the early 1970s his short stories began to focus increasingly on sporting and fishing. He published numerous stories in and other outdoor magazines, and two of these stories were so popular that they were extended for publication as short books. first published in in 1970, told the parallel tales of the sex lives of salmon and salmon fishermen in England. The second tale, first appeared in in 1978, and related the personal battle between Humphrey and a great elusive trout.

While chronicled the progress and change of a Texas family over several generations, Humphrey's next novel, (1973), showed the demise and dissolution of the Renshaw clan as its matriarch dies and the family's secrets are revealed. In (1977), Humphrey made his final literary trip to Clarksville, recounting the day of his father's fatal wreck and the lives of his family leading up to the event. Considered by many to be his finest work, it often draws comparisons to James Agee's as a touching remembrance of a young boy's reaction to his father's death.

Humphrey continued his hard look at death and its impact on those left behind in a novel based in part on the suicide of a close friend's son. (1984) takes place on a weekend fishing trip, during which a man relives the previous year in which he attempted suicide following the suicides of his son and his best friend and the breakup of his marriage.

Humphrey followed with two books containing, for the most part, previously published short stories. (1985) included works from his first publication, , and from . (1986) drew from his numerous sporting and outdoors articles and included his two small books and . Humphrey's final novel, (1989), was historical fiction based on the forced migration of Cherokee Indians to Texas and then Oklahoma.

The 20 short stories in Humphrey's final published book (1992) cover a wide range of topics, but uniformly convey his sense of frustration over his declining health and increasing age. As he approached his 70th birthday, he suffered continued loss of hearing and underwent repeated treatments for skin cancer. Diagnosed with cancer of the larynx in April 1997, he died on August 20th of that year.