He is best known for his writings about California politics and culture, including the condition of migrant farm workers and the internment of Japanese Americans during World War II.

During the 1920s and early 1930s, McWilliams joined a loose network of mostly Southern California writers that included Robinson Jeffers, John Fante, Louis Adamic, and Upton Sinclair.

Mencken provided an outlet for McWilliams's early journalism and floated the idea for his first book, a 1929 biography of popular writer and sometime Californian Ambrose Bierce.

He began working with left-wing political and legal organizations, including the American Civil Liberties Union and the National Lawyers Guild.

He continued to represent workers in and around Los Angeles, helped organize unions and guilds, and served as a trial examiner for the new National Labor Relations Board.

Once out of government, McWilliams became an outspoken critic of the removal and internment of Japanese American citizens and almost immediately began writing an exposé on the topic.

Published in 1944, Prejudice: Japanese-Americans: Symbol of Racial Intolerance was cited by Justice Frank Murphy in his dissenting opinion in Korematsu v. United States, the Supreme Court decision that upheld the constitutionality of the exclusion.

Shortly before its publication, McWilliams accepted an offer from incoming Governor Culbert Olson to head California's Division of Immigration and Housing.

Over his four-year term (1938–1942), he focused on improving agricultural working conditions and wages, but his hopes for major reform deteriorated with the advent of World War II.

McWilliams left his government post in 1942, when incoming Governor Earl Warren promised campaign audiences that his first official act would be to fire him.

No such conversion occurred in his attitude toward another California politician, Richard Nixon, whom McWilliams described in 1950 as "a dapper little man with an astonishing capacity for petty malice."

He turned his attention to issues of racial and ethnic equality, writing a series of important books (including Brothers Under the Skin, Prejudice, North from Mexico, and A Mask for Privilege) that dealt with the treatment of immigrant and minority groups.

Several years later, a group of Los Angeles screenwriters, directors, and producers known as the Hollywood Ten was cited for contempt of Congress after refusing to answer a House committee's questions about Communist Party membership.