Millar was born in Los Gatos, California, and raised in his parents' native Kitchener, Ontario, Canada, where he started college. When his father abandoned his family unexpectedly, Macdonald lived with his mother and various relatives, moving several times by his sixteenth year. The prominence of broken homes and domestic problems in his fiction has its roots in his youth.

In Canada, he met and married Margaret Sturm in 1938. They had a daughter, Linda, who died in 1970. He began his career writing stories for pulp magazines. Millar attended the University of Michigan, where he earned a Phi Beta Kappa key and a Ph.D. in literature. While doing graduate study, he completed his first novel, The Dark Tunnel, in 1944. At this time, he wrote under the name John Macdonald, in order to avoid confusion with his wife, who was achieving her own success writing as Margaret Millar. He then changed briefly to John Ross Macdonald before settling on Ross Macdonald, in order to avoid mixups with contemporary John D. MacDonald. After serving at sea as a naval communications officer from 1944 to 1946, he returned to Michigan, where he obtained his Ph.D. degree.

Macdonald's popular detective Lew Archer derives his name from Sam Spade's partner, Miles Archer, and from Lew Wallace, author of A Tale of the Christ. Macdonald first introduced the tough but humane private eye in the 1946 short story "Find the Woman". A full-length novel, The Moving Target, followed in 1949. This novel (the first in a series of eighteen) would become the basis for the 1966 Paul Newman film Harper. In the early 1950s, he returned to California, settling for some thirty years in Santa Barbara, the area where most of his books were set. (Macdonald's fictional name for Santa Barbara was Santa Teresa; this "pseudonym" for the town was subsequently resurrected by Sue Grafton, whose "alphabet novels" are also set in Santa Teresa.) The very successful Lew Archer series, including bestsellers The Goodbye Look, The Underground Man, and Sleeping Beauty, concluded with The Blue Hammer in 1976. Macdonald died of Alzheimer's disease in Santa Barbara, California.

Macdonald is the primary heir to Dashiell Hammett and Raymond Chandler as the master of American hardboiled mysteries. His writing built on the pithy style of his predecessors by adding psychological depth and insights into the motivations of his characters. Macdonald's plots were complicated, and often turned on Archer's unearthing family secrets of his clients and of the criminals who victimized them. Lost or wayward sons and daughters were a theme common to many of the novels. Macdonald deftly combined the two sides of the mystery genre, the "whodunit" and the psychological thriller. Even his regular readers seldom saw a Macdonald denouement coming.

Inspired by F. Scott Fitzgerald, Macdonald's writing was hailed by genre fans and literary critics alike. Author William Goldman called his works "the finest series of detective novels ever written by an American".

Lew Archer novels

• The Moving Target - 1949 (filmed with Paul Newman as Harper, 1966)
• The Drowning Pool - 1950 (also filmed with Paul Newman as "Lew Harper", 1975)
• The Way Some People Die - 1951
• The Ivory Grin (aka Marked for Murder) - 1952
• Find a Victim - 1954
• The Barbarous Coast - 1956
• The Doomsters - 1958
• The Galton Case - 1959
• The Wycherly Woman - 1961
• The Zebra-Striped Hearse - 1962
• The Chill - 1964
• The Far Side of the Dollar - 1965
• Black Money - 1966
• The Instant Enemy - 1968
• The Goodbye Look - 1969
• The Underground Man - 1971 (filmed as a television series pilot in 1974)
• Sleeping Beauty - 1973
• The Blue Hammer - 1976

Lew Archer short stories

• The Name is Archer (paperback original containing 7 stories) - 1955
• Private Investigator (The Name is Archer + 2 additional stories) - 1977
• Strangers in Town (Two of the three short stories include Lew Archer) - 2001

Lew Archer omnibuses

• Archer in Hollywood - 1967
• Archer at Large - 1970
• Archer in Jeopardy - 1979

Other novels

writing as John Macdonald

• The Dark Tunnel (aka I Die Slowly) - 1944
• Trouble Follows Me (aka Night Train) - 1946
• Blue City - 1947
• The Three Roads - 1948

writing as Ross Macdonald

• Meet Me at the Morgue (aka Experience With Evil) - 1953
• The Ferguson Affair - 1960