Born to a British father and an Irish mother, he was raised in Somerset. His education was slender because of a broken home followed by World War II, when many English schools were in chaos, finally leaving at the age of 15, when he became a messenger boy for the Yorkshire Post.

In a 30-year journalistic career Humphry worked and wrote for the Bristol Evening World, the Manchester Evening News, the Daily Mail, the Sunday Times and, lastly, the Los Angeles Times.

His first wife, Jean Humphry, ended her life on March 29, 1975, in The Cotswolds with her husband at her side, with an intentional overdose of medication; she was suffering from terminal breast cancer. He told that story from his perspective in the best-selling Jean's Way. Derek and Jean Humphry had three sons, the youngest one an adoptee.

Humphry wrote the 1991 suicide handbook, Final Exit. From 1993 onwards Humphry has been president of the Euthanasia Research & Guidance Organization (ERGO), and chairs the advisory board of the new Final Exit Network (formed 2004 to replace the Hemlock Society dissolved the previous year in mergers).

His marriage to his next wife, Ann Wickett, an American and a co-founder of the Hemlock Society, ended in 1989 when she filed for divorce; they had no children. Ann Wickett committed suicide, at the age of 49 on October 2, 1991, during a recurrence of depression and Borderline Personality Disorder. She had been battling breast cancer, but the cancer was in remission and she was not considered "terminally ill". In her suicide note, she claimed that Humphry was a "killer" and that his first wife, Jean, had died of suffocation.

In early 1991 Humphry married Gretchen Crocker, youngest daughter of a Oregon farming family.

Humphry is an advisor to the World Federation of Right to Die Societies by virtue of his past presidency and in appreciation of his 26 years of involvement with that organization.

Since it was founded in 2004, Humphry has been an adviser to the Final Exit Network. When four members of the organization were accused in Georgia of assisting a suicide he launched the Final Exit Liberty Fund.

"Humphry ranks as one of the preeminent pioneers of the American euthanasia movement."

"Derek Humphry is widely acknowledged to be the initiator of the euthanasia reform movement in the United States."

Although he himself had no higher education, Derek Humphry has been a guest lecturer at Harvard, Princeton, Stanford, Chicago, Michigan, UCLA and USC, among others.

Interviews with Humphry have been published in a multitude of magazines including Playboy, Time, Newsweek, People, Esquire and U.S. News & World Report. He has been interviewed on US television programs including 60 Minutes, The Larry King Show, Donahue and Face the Nation.

Humphry was newsletter editor for the World Federation of Right to Die Societies for a number of years.

As of 2009, the paperback Final Exit was in print in English, Spanish and Italian. It has sold more than one million copies in twelve languages. In April 2007 the editors and book critics of USA Today selected Final Exit as one of the most memorable 25 books of the last quarter century.

In 2008 he completed his autobiography, Good Life, Good Death: Memoir of an Investigative Reporter and Pro-choice Advocate (ISBN 978-0-9768283-3-4).