Mencken attended a Baltimore private school and the Baltimore Polytechnic. He became a reporter for the Baltimore Morning Herald in 1899 and in 1906 joined the staff of the Baltimore Sun, where he worked at intervals throughout most of his life. From 1914 to 1923 he coedited (with George Jean Nathan) The Smart Set, a witty, urban magazine influential in the growth of American literature, and in 1924 he and Nathan founded the American Mercury, which Mencken edited until 1933.

Mencken was probably the most influential American literary critic in the 1920s, and he often used his criticism as a point of departure to jab at various American social and cultural weaknesses. His reviews and miscellaneous essays filled six volumes aptly titled Prejudices (1919–27). In literature he fought against what he regarded as fraudulently successful writers and worked for the recognition of such outstanding newcomers as Theodore Dreiser and Sinclair Lewis. He jeered at American sham, pretension, provincialism, and prudery, and he ridiculed the nation's organized religion, business, and middle class (or “booboisie”).

Mencken's caustic view of life remained with him throughout his career, and in the 1930s and '40s he altered considerably less than the world around him, with the result that his influence almost disappeared. Few people found the Great Depression a subject for satire of any sort, yet he was as satirical about President Franklin D. Roosevelt and the New Deal as he had been about President Herbert Hoover and Prohibition. Similarly, when the German culture that he had enjoyed was marred by Adolf Hitler and Nazism, Mencken was slower than some of his public to recognize it and to take the fact seriously.

Mencken made still another contribution to American culture. In 1919 he had published a solid volume, The American Language, an attempt to bring together examples of American, rather than English, expressions and idioms. The book at once attracted attention. It grew with each reissue through the years, and in 1945 and 1948 Mencken published substantial supplements. By the time of his death, he was perhaps the leading authority on the language of his country.

Mencken's autobiographical trilogy, Happy Days (1940), Newspaper Days (1941), and Heathen Days (1943), is devoted to his experiences in journalism.