LaGuardia was born in The Bronx to an Italian lapsed-Catholic father and a Hungarian mother of Jewish origin from Trieste, and he was raised an Episcopalian. His middle name was changed to Henry (the English form of Enrico) when he was a child. He spent most of his childhood in Prescott, Arizona. The family moved to his mother's hometown of Trieste, Italy, after his father was discharged from his bandmaster position in the U.S. Army in 1898. LaGuardia served in U.S. consulates in Budapest, Trieste, and Fiume (1901-1906). Fiorello returned to the U.S. to continue his education at New York University, and during this time he worked for New York Society for the Prevention of Cruelty for Children and as a translator for the U.S. Immigration Service at Ellis Island (1907-1910).

He became the Deputy Attorney General of New York in 1914. In 1916 he was elected to the U.S. House of Representatives where he developed a reputation as a fiery and devoted reformer. In Congress, LaGuardia represented then-Italian East Harlem.

La Guardia briefly (1917 - 1919) served in the armed forces, commanding a unit of the United States Army Air Service on the Italian/Austrian front in World War I, rising to the rank of major.

In 1921 his wife died of tuberculosis, LaGuardia having nursed her through the 17 month ordeal grew depressed, and turned to the bottle and spent most of the year following her death on an alcoholic binge. He recovered and became a teetotaler.

LaGuardia ran for, and won, a seat in Congress again in 1922. Extending his record as a reformer, LaGuardia sponsored labor legislation and railed against immigration quotas. He was overwhelmingly defeated by incumbent Jimmy Walker in the 1929 mayoral election. In 1932, along with Sen. George Norris (R-NE), Rep. LaGuardia sponsored the Norris-LaGuardia Act.

LaGuardia was elected mayor of New York City on an anti-corruption "fusion" ticket during the Great Depression, which united him in an uneasy alliance with New York's Jews and liberal bluebloods (Wasps). These included the famed architect and New York historian Isaac Newton Phelps-Stokes whose patrician manners LaGuardia detested. Surprisingly, the two men became friends. Phelps-Stokes had personally nursed his wife during the last five years of her life, during which she was paralysed and speechless due to a series of strokes. On learning of Phelps-Stokes's ordeal, so like his own, LaGuardia ceased all bickering and the two developed genuine affection for each other.

LaGuardia was hardly an orthodox Republican. He also ran as the nominee of the American Labor Party, a union-dominated anti-Tammany grouping that also ran FDR for President from 1936 onward. LaGuardia also supported Roosevelt.

LaGuardia was the city's first Italian-American mayor, but LaGuardia was far from being a typical Italian New Yorker. After all, he was a Republican Episcopalian who had grown up in Arizona, and had an Istrian Jewish mother and a Roman Catholic-turned-atheist Italian father. He reportedly spoke seven languages, including Hebrew, Hungarian, Italian, and Yiddish.

LaGuardia is famous for, among other things, restoring the economic lifeblood of New York City during and after the Great Depression. His massive public works programs employed thousands of unemployed New Yorkers and his constant lobbying for federal government funds allowed New York to establish the foundation for its economic infrastructure. He was also well known for reading the comics on the radio during a newspaper strike, and pushing to have a commercial airport (Floyd Bennett Field, and now LaGuardia Airport) within city limits. He was also a very outspoken and early critic of Hitler and the Nazi regime. In a public address as early as 1934, LaGuardia warned, "Part of program is the complete annihilation of the Jews in Germany." In 1937, speaking before the Women’s Division of the American Jewish Congress, LaGuardia called for the creation of a special pavilion at the upcoming New York World’s Fair: "a chamber of horrors" for "that brown-shirted fanatic."

LaGuardia was the director general for the UNRRA in 1946.

LaGuardia loved music and conducting, and was famous for spontaneously conducting professional and student orchestras that he visited. He once said that the "most hopeful accomplishment" of his long administration as mayor was the creation of the High School of Music & Art in 1936, now the Fiorello H. LaGuardia High School of Music & Art and Performing Arts. In addition to LaGuardia High School, a number of other instututions are also named for him, including LaGuardia Community College. He was also the subject of the Pulitzer Prize-winning Broadway musical Fiorello!. He died in New York City of pancreatic cancer at the age of 64.