Mencken's home at 1524 Hollins Street in Baltimore's Union Square neighborhood, where he lived for sixty-seven years before his death in 1956, was bequeathed to the University of Maryland, Baltimore on the death of his younger brother, August, in 1967. The City of Baltimore acquired the property in 1983, and the H. L. Mencken House became part of the City Life Museums. It has been closed to general admission since 1997, but is opened for special events and group visits by arrangement.

He began his primary education in the mid-1880s at Professor Knapp's School, located on the east side of Holliday Street between East Lexington and Fayette Streets, next to the Holliday Street Theatre and across from the newly constructed Baltimore City Hall. The site today is the War Memorial and City Hall Plaza laid out in 1926 in memory of World War I dead. At fifteen, in June 1896, he graduated as valedictorian from the Baltimore Polytechnic Institute, at the time a males-only mathematics, technical and science-oriented public high school.

He worked for three years in his father's cigar factory. He disliked the work, especially the sales aspect of it, and resolved to leave, with or without his father's blessing. In early 1898 he took a class in writing at one of the country's first correspondence schools, the Cosmopolitan University. This was to be the entirety of Mencken's formal education in journalism, or in any other subject. Upon his father's death a few days after Christmas in the same year, the Business reverted to his uncle, and Mencken was free to pursue his career in journalism. He had applied in February 1899 to the Morning Herald newspaper (which became the Baltimore Morning Herald in 1900) and had been hired as a part-timer there, but still kept his position at the factory for a few months. In June he was hired as a full-time reporter.

Mencken served as a reporter at the Herald for six years. Less than two and a half years after the Great Baltimore Fire, the paper was purchased in June 1906 by Charles H. Grasty, the owner and Editor of The News since 1892, and competing owner and publisher Gen. Felix Agnus, of the town's oldest (since 1773) and largest daily, The Baltimore American. They proceeded to divide the staff, assets and resources of The Herald between them. Mencken then moved to The Baltimore Sun, where he worked for Charles H. Grasty. He continued to contribute to The Sun, The Evening Sun (founded 1910) and The Sunday Sun full-time until 1948, when he stopped writing after suffering a stroke.

Mencken began writing the editorials and opinion pieces that made his name at The Sun. On the side, he wrote short stories, a novel, and even poetry, which he later revealed. In 1908, he became a literary critic for The Smart Set magazine, and in 1924 he and George Jean Nathan founded and edited The American Mercury, published by Alfred A. Knopf. It soon developed a national circulation and became highly influential on college campuses across America. In 1933, Mencken resigned as Editor.

Mencken also published many works under various pseudonyms, including Owen Hatteras, John H Brownell, william Drayham, WLD Bell, and Charles Angoff. As a ghostwriter for the physician Leonard K. Hirshberg, he wrote a series of articles and (in 1910) most of a book about the care of babies.

Mencken countered the arguments for Anglo-Saxon superiority prevalent in his time in a 1923 essay entitled "The Anglo-Saxon", which argued that if there was such a thing as a pure "Anglo-Saxon" race, it was defined by its inferiority and cowardice. "The normal American of the 'pure-blooded' majority goes to rest every night with an uneasy feeling that there is a burglar under the bed and he gets up every morning with a sickening fear that his underwear has been stolen."

As a frank admirer of Nietzsche, Mencken was a detractor of populism and representative democracy, which he believed was a system in which inferior men dominated their superiors. As did Nietzsche, he also spoke out against religious belief (and as a fervent nonbeliever, against the very notion of a deity), particularly Christian fundamentalism, Christian Science and creationism, and against the "Booboisie," his word for the ignorant middle classes. In the summer of 1925, he attended the famous Scopes "Monkey Trial" in Dayton, Tennessee, and wrote scathing columns for the Baltimore Sun (widely syndicated) and American Mercury mocking the anti-evolution Fundamentalists (especially william Jennings Bryan). The play Inherit the Wind is a fictionalized version of the trial, and, as noted above, the cynical reporter E.K. Hornbeck is based on Mencken. In 1926, he deliberately had himself arrested for selling an issue of The American Mercury that was banned in Boston under the Comstock laws. Mencken heaped scorn not only on the public officials he disliked, but also on the contemporary state of American elective politics itself.

In the summer of 1926, Mencken followed with great interest the Los Angeles grand jury inquiry into the famous Canadian-American evangelist Aimee Semple McPherson. She was accused of faking her reported kidnapping and the case attracted national attention. There was every expectation Mencken would continue his previous pattern of anti-fundamentalist articles, this time with a searing critique of McPherson. Unexpectedly, he came to her defense, identifying various local religious and civic groups which were using the case as an opportunity to pursue their respective ideological agendas against the embattled Pentecostal minister. He spent several weeks in Hollywood, California, and wrote many scathing and satirical columns on the movie industry and the southern California culture. After all charges had been dropped against McPherson, Mencken revisited the case in 1930 with a sarcastically biting and observant article. He wrote that since many of that town's residents acquired their ideas "of the true, the good and the beautiful" from the movies and newspapers, "Los Angeles will remember the testimony against her long after it forgets the testimony that cleared her."

The Sara Haardt Mencken collection at Goucher College includes letters exchanged between Haardt and Mencken and condolences written after her death. Some of Mencken's vast literary correspondence is held at the New York Public Library. "Gift of HL Mencken 1929" is stamped on the Marriage of Heaven and Hell, Luce 1906 edition of william Blake, which shows up from the Library of Congress online version for reading.

In the 1930 edition of Treatise on the Gods, Mencken wrote:

In 1931 the Arkansas legislature passed a motion to pray for Mencken's soul after he had called the state the "apex of moronia."

Mencken admired German Philosopher Friedrich Nietzsche (he was the first Writer to provide a scholarly analysis in English of Nietzsche's views and writings) and Joseph Conrad. His humor and satire owe much to Ambrose Bierce and Mark Twain. He did much to defend Dreiser despite freely admitting his faults, including stating forthrightly that Dreiser often wrote badly and was a gullible man. Mencken also expressed his appreciation for william Graham Sumner in a 1941 collection of Sumner's essays, and regretted never having known Sumner personally. In contrast, Mencken was scathing in his criticism of the German Philosopher Hans Vaihinger, whom he described as "an extremely dull author" and whose famous book Philosophy of 'As If' he dismissed as an unimportant "foot-note to all existing systems."

On November 23, 1948, Mencken suffered a stroke, which left him aware and fully conscious but nearly unable to read or write and able to speak only with difficulty. After his stroke, Mencken enjoyed listening to Classical music and, after some recovery of his ability to speak, talking with friends, but he sometimes referred to himself in the past tense, as if he were already dead. During the last year of his life, his friend and biographer william Manchester read to him daily.

Shortly after World War II, Mencken expressed his intention of bequeathing his books and papers to Baltimore's Enoch Pratt Free Library. At his death, it was in possession of most of the present large collection. As a result, his papers as well as much of his personal library, which includes many books inscribed by major authors, are held in the Library's Central Branch on Cathedral Street in Baltimore. The original third floor H. L. Mencken Room and Collection housing this collection was dedicated on April 17, 1956. The new Mencken Room, on the first floor of the Library's Annex, was opened in November 2003.

Preoccupied as Mencken was with his legacy, he organized his papers, letters, newspaper clippings and columns, even grade school report cards. After his death, these materials were made available to scholars in stages in 1971, 1981, and 1991, and include hundreds of thousands of letters sent and received; the only omissions were strictly personal letters received from women.

In 1989, per his instructions, Alfred A. Knopf published Mencken's "secret diary" as The Diary of H. L. Mencken. According to an Associated Press story, Mencken's views shocked even the "sympathetic scholar who edited it," Charles A. Fecher of Baltimore. There is a club in Baltimore called the Maryland Club which had one Jewish member, and that member died. Mencken said, "There is no other Jew in Baltimore who seems suitable," according to the article. The diary also quoted him as saying of blacks, in September 1943, that "it is impossible to talk anything resembling discretion or judgment to a colored woman. They are all essentially child-like, and even hard experience does not teach them anything."

Other Mencken related collections of note are at Dartmouth College, Harvard University, Princeton University, Johns Hopkins University, and Yale University. In 2007, Johns Hopkins acquired "nearly 6,000 books, photographs and letters by and about Mencken" from "the estate of an Ohio accountant."

The H.L. Mencken Club was founded in Elizabethtown, Pennsylvania in 2008. The organization was founded by Paul Gottfried, the current President.

Elsewhere, he spoke of the nonsense of higher mathematics and "probability" theory, after he read Angoff's article for Charles S. Peirce in the American Mercury. "So you believe in that garbage, too—theories of knowledge, infinity, laws of probability. I can make no sense of it, and I don't believe you can either, and I don't think your god Peirce knew what he was talking about."

Mencken also ridiculed Einstein’s theory of general relativity, saying "in the long run his curved space may be classed with the psychosomatic bumps of Gall and Spurzheim". In his private letters, he said: