Born in St. Louis, Missouri, he moved with his family to New York City, where he received his art training. In 1924 he traveled to Paris and London, where he studied painting, drawing and sculpture. When he returned to the United States, a friend showed one of his drawings to an editor at the New York Herald Tribune, which got him commissions for that newspaper and the New York Times.

Hirschfeld's art style is unique, and he is considered to be one of the most important figures in contemporary caricature, having influenced countless cartoonists. Hirschfeld's caricatures are almost always drawings of pure line, with simple black ink on white paper, with little to no shading or cross-hatching. His drawings always manage to capture a likeness using the minimum number of lines. Though his caricatures often exaggerate and distort the faces of his subjects, he is often described as being a fundamentally "nicer" caricaturist than many of his contemporaries, and being drawn by Hirschfeld was considered an honor more than an insult.

During Hirschfeld's nearly eight-decade career, he gained fame by illustrating the entire casts of various Broadway plays, which would appear to accompany reviews in the Times. Though this was Hirschfeld's best known field of interest, he also would draw politicians, TV stars, and celebrities of all stripes from Cole Porter, the Nordstrom Sisters to the cast of Star Trek: The Next Generation. He expanded his audience by contributing to the Patrick F. McManus humor column in Outdoor Life magazine for a number of years.

Hirschfeld is known for hiding the name of his daughter, Nina, in all of the drawings he produced since her birth in 1945. The name would appear in a sleeve, in a hairdo, or somewhere in the background. Sometimes "NINA" would show up more than once, but Hirschfeld would helpfully add a number next to his signature, to let people know how many times her name would appear. Hirschfeld originally intended the NINA gag to be a one-time gimmick but it soon spiraled out of control. Though the NINAs were a popular feature in his cartoons, with many enjoying the game of searching for them, on more than one occasion Hirschfeld would lament that the gimmick had overshadowed his art. On occasion he did try to discontinue the practice, but such attempts always generated harsh criticism.

Hirschfeld collaborated with humorist S. J. Perelman on several projects, including Westward Ha! Or, Around the World in 80 Cliches, a satirical look at the duo's travels on assignment for Holiday magazine.

In 1991, the United States Postal Service commissioned Hirschfeld to draw a series of postage stamps commemorating famous American comedians. The collection included drawings of Stan Laurel, Oliver Hardy, Edgar Bergen (with Charlie McCarthy), Jack Benny, Fanny Brice, Bud Abbott and Lou Costello. He followed that up with a collection of silent film stars including Rudolph Valentino, ZaSu Pitts and Buster Keaton. The Postal Service allowed him to include Nina's name in his drawings, the only time a person's name has been hidden in a postage stamp in the United States.

Permanent collections of Hirschfeld's work appear at the Metropolitan Museum of Art and the Museum of Modern Art in New York.

Hirschfeld has a star on the St. Louis Walk of Fame.

He died of natural causes at his home in New York City at the age of 99 on January 20, 2003. His late wife, Broadway actress/performer Dolly Haas, mother of Nina, died of ovarian cancer in 1994 at the age of 84, and he never lost his anger over her painful death.