In spite of an impoverished background, young Long managed to obtain enough formal schooling to pass the bar examination in 1915. He was politically ambitious and won election to the state railroad commission at age 25. In this post his calls for the equitable regulation of the state utility companies and his attacks on Standard Oil earned him widespread popularity. He ran for the Louisiana governorship in 1924 and was defeated, but in 1928 he won the governorship through the heavy support of the discontented rural districts. His picturesque if irreverent speech, fiery oratory, and unconventional buffoonery soon made him nationally famous, and he was widely known by his nickname, “Kingfish.” Long made a genuine contribution with an ambitious program of public works and welfare legislation in a state whose road system and social services had been sadly neglected by the wealthy elite that had long controlled the state government. Always the champion of poor whites, he effected a free-textbook law, launched a massive and very useful program of road and bridge building, expanded state university facilities, and erected a state hospital where free treatment for all was intended. He was opposed to excessive privileges for the rich, and he financed his improvements with increased inheritance and income taxes as well as a severance tax on oil—earning him the bitter enmity of the wealthy and of the oil interests.

Long's folksy manner and sympathy for the underprivileged diverted attention from his ruthless autocratic methods. Surrounding himself with gangsterlike bodyguards, he dictated outright to members of the legislature, using intimidation if necessary. When he was about to leave office to serve in the U.S. Senate (1932), he fired the legally elected lieutenant governor and replaced him with two designated successors who would obey him from Washington. In order to fend off local challenges to his control in 1934, he effected radical changes in the Louisiana government, abolishing local government and taking personal control of all educational, police, and fire job appointments throughout the state. He achieved absolute control of the state militia, judiciary, and election and tax-assessing apparatus, while denying citizens any legal or electoral redress.

In the Senate (1932–35) he sought national power with a Share-the-Wealth program (“every man a king”), which was tempting to a depression-shocked public. Had Long been able to unite the various nationwide radical movements, a private poll taken in the spring of 1935 estimated that he would have won up to 4 million votes in the next year's presidential election, thus wielding a balance of power between the two major parties.

Long was at the height of his power when assassinated by Carl Austin Weiss, the son of a man whom he had vilified. The Long political dynasty was carried on by his brother, Earl K. Long, who served as governor (1939–40, 1948–52, 1956–60), and his son, Russell B. Long, who served in the U.S. Senate from 1948 to 1987.