Henry Louis Mencken was born in Baltimore, Maryland, the son of August Mencken, Sr. and Ann Margaret (Abhau) Mencken. He graduated as valedictorian from the Baltimore Polytechnic Institute in 1896 and then spent 3 years working in his father's cigar factory. Thereafter he received a job at the Morning Herald newspaper, where he served as a reporter for 6 years.

Mencken worked for the Baltimore Sun, The Evening Sun, and The Sunday Sun from the early 1900s until 1948, when he suffered a stroke; he also in 1908 became literary critic for The Smart Set magazine. In 1924 he founded and began editing The American Mercury (AM) with George Jean Nathan, published by Alfred A. Knopf. The magazine quickly developed a national circulation, particularly on college campuses. Mencken resigned as editor from AM in 1933.

Mencken was briefly married in the 1930s to Sara Haardt; she died of meningitis in 1935. After Mencken's stroke in 1948, he was nearly unable to read or write and could speak only with difficulty. After his stroke his secretary, Mrs Lohrfink, acted as an amanuensis, writing his letters in the third-person. Prior to that, he had often dictated letters to his secretary or to an office secretary.