Twain was raised in Hannibal, Missouri, which later provided the setting for both Tom Sawyer and Huckleberry Finn. He served an apprenticeship with a printer early in his career, and then worked as a typesetter, contributing articles to his older brother Orion Clemens' newspaper. Twain then became a riverboat pilot on the Mississippi River, which provided him the material for Life on the Mississippi (1883). Soon after, Twain headed west to join Orion in Nevada. He referred humorously to his lack of success at mining, turning to journalism for the Virginia City Territorial Enterprise.

He first achieved success as a writer with the humorous story "The Celebrated Jumping Frog of Calaveras County," which was published in 1865; it was based on a story that he heard at Angels Hotel in Angels Camp, California, where he had spent some time while he was working as a miner. The short story brought him international attention. He wrote both fiction and non-fiction. As his fame grew, he became a much sought-after speaker. His wit and satire, both in prose and in speech, earned praise from critics and peers, and Twain was a friend to presidents, artists, industrialists, and European royalty.

Although Twain initially spoke out in favor of American interests in the Hawaiian Islands, he later reversed his position, going on to become vice president of the American Anti-Imperialist League from 1901 until his death in 1910, coming out strongly against the Philippine-American War and colonialism.

Twain earned a great deal of money from his writing and lectures, but invested in ventures that lost most of it, such as the Paige Compositor, a mechanical typesetter that failed because of its complexity and imprecision. He filed for bankruptcy in the wake of these financial setbacks, but in time overcame his financial troubles with the help of Standard Oil executive Henry Huttleston Rogers. Twain eventually paid all his creditors in full, even though his declaration of bankruptcy meant he was not required to do so. He was born shortly after an appearance of Halley's Comet, and predicted that his death would accompany it as well, dying a day after the comet was at its closest to Earth.

Samuel Langhorne Clemens was born on November 30, 1835, in Florida, Missouri. He was the sixth of seven children of Jane (née Lampton; 1803–1890), a native of Kentucky, and John Marshall Clemens (1798–1847), a native of Virginia.^]

His parents met when his father, a lawyer called to the bar in Kentucky, tried to help Jane's father and uncle avoid bankruptcy. They were married in 1823. Twain was of English and Scots-Irish descent. Only three of his siblings lived beyond childhood: Orion (1825–1897), Pamela (1827–1904), and Henry (1838–1858). His brother Pleasant Hannibal (1828) died at three weeks of age, his sister Margaret (1830–1839) when Twain was three, and his brother Benjamin (1832–1842) three years later.

When he was four, Twain's family moved to Hannibal, Missouri, a port town on the Mississippi River that inspired the fictional town of St. Petersburg in The Adventures of Tom Sawyer and The Adventures of Huckleberry Finn. Slavery was legal in Missouri at the time, and it became a theme in these writings. His father was an attorney and judge who died of pneumonia in 1847, when Twain was 11. The following year, Twain left school after the fifth grade to become a printer's apprentice. In 1851, he began working as a typesetter, contributing articles and humorous sketches to the Hannibal Journal, a newspaper that Orion owned. When he was 18, he left Hannibal and worked as a printer in New York City, Philadelphia, St. Louis, and Cincinnati, joining the newly formed International Typographical Union, the printers trade union. He educated himself in public libraries in the evenings, finding wider information than at a conventional school.

Twain describes his boyhood in Life on the Mississippi, stating that "there was but one permanent ambition" among his comrades: to be a steamboatman. "Pilot was the grandest position of all. The pilot, even in those days of trivial wages, had a princely salary – from a hundred and fifty to two hundred and fifty dollars a month, and no board to pay." As Twain described it, the pilot's prestige exceeded that of the captain. The pilot had to "get up a warm personal acquaintanceship with every old snag and one-limbed cottonwood and every obscure wood pile that ornaments the banks of this river for twelve hundred miles; and more than that, must... actually know where these things are in the dark". Steamboat pilot Horace E. Bixby took Twain on as a cub pilot to teach him the river between New Orleans and St. Louis for $500 (equivalent to $18,000 in 2023), payable out of Twain's first wages after graduating. Twain studied the Mississippi, learning its landmarks, how to navigate its currents effectively, and how to read the river and its constantly shifting channels, reefs, submerged snags, and rocks that would "tear the life out of the strongest vessel that ever floated". It was more than two years before he received his pilot's license. Piloting also gave him his pen name from "mark twain", the leadsman's cry for a measured river depth of two fathoms (12 feet), which was safe water for a steamboat.

As a young pilot, Clemens served on the steamer A. B. Chambers with Grant Marsh, who became famous for his exploits as a steamboat captain on the Missouri River. The two liked and admired each other, and maintained a correspondence for many years after Clemens left the river.

While training, Samuel convinced his younger brother Henry to work with him, and even arranged a post of mud clerk for him on the steamboat Pennsylvania. On June 13, 1858, the steamboat's boiler exploded; Henry succumbed to his wounds on June 21. Twain claimed to have foreseen this death in a dream a month earlier,^? which inspired his interest in parapsychology; he was an early member of the Society for Psychical Research. Twain was guilt-stricken and held himself responsible for the rest of his life. He continued to work on the river and was a river pilot until the Civil War broke out in 1861, when traffic was curtailed along the Mississippi River. At the start of hostilities, he enlisted briefly in a local Confederate unit. He later wrote the sketch "The Private History of a Campaign That Failed", describing how he and his friends had been Confederate volunteers for two weeks before their unit disbanded.

He then left for Nevada to work for his brother Orion, who was Secretary of the Nevada Territory. Twain describes the episode in his book Roughing It.

Raymond was twice married, first to actress Marie E. Gordon, known on the stage after 1864. Their marriage was unhappy and they were legally separated. His second wife was a daughter of Rose Eytinge. At the time of his second marriage he obtained legal authority for the change of his name from John O'Brien to John T. Raymond. In 1887 his body was brought to New York, and buried in the Actors' Plot, in Evergreen Cemetery, Long Island. His grave is marked by a stone bearing an inscription and an epitaph written by William Winter.