The New Yorker was founded by Harold Ross (1892–1951) and his wife Jane Grant (1892–1972), a New York Times reporter, and debuted on February 21, 1925. Ross wanted to create a sophisticated humor magazine that would be different from perceivably "corny" humor publications such as Judge, where he had worked, or the old Life. Ross partnered with entrepreneur Raoul H. Fleischmann (who founded the General Baking Company) to establish the F-R Publishing Company. The magazine's first offices were at 25 West 45th Street in Manhattan. Ross edited the magazine until his death in 1951. During the early, occasionally precarious years of its existence, the magazine prided itself on its cosmopolitan sophistication. Ross declared in a 1925 prospectus for the magazine: "It has announced that it is not edited for the old lady in Dubuque."

The New Yorker has featured cartoons (usually gag cartoons) since it began publication in 1925. For years, its cartoon editor was Lee Lorenz, who first began cartooning in 1956 and became a New Yorker contract contributor in 1958. After serving as the magazine's art editor from 1973 to 1993 (when he was replaced by Françoise Mouly), he continued in the position of cartoon editor until 1998. His book The Art of the New Yorker: 1925–1995 (Knopf, 1995) was the first comprehensive survey of all aspects of the magazine's graphics. In 1998, Robert Mankoff took over as cartoon editor and edited at least 14 collections of New Yorker cartoons. Mankoff also usually contributed a short article to each book, describing some aspect of the cartooning process or the methods used to select cartoons for the magazine. He left the magazine in 2017.

The New Yorker's stable of cartoonists has included many important talents in American humor, including Charles Addams, Peter Arno, Charles Barsotti, George Booth, Roz Chast, Tom Cheney, Sam Cobean, Leo Cullum, Richard Decker, Pia Guerra, J. B. Handelsman, Helen E. Hokinson, Pete Holmes, Ed Koren, Reginald Marsh, Mary Petty, George Price, Charles Saxon, Burr Shafer, Otto Soglow, William Steig, Saul Steinberg, James Stevenson, James Thurber, and Gahan Wilson.

Many early New Yorker cartoonists did not caption their cartoons. In his book The Years with Ross, Thurber describes the newspaper's weekly art meeting, where cartoons submitted over the previous week were brought up from the mail room to be looked over by Ross, the editorial department, and a number of staff writers. Cartoons were often rejected or sent back to artists with requested amendments, while others were accepted and captions were written for them. Some artists hired their own writers; Helen Hokinson hired James Reid Parker in 1931. Brendan Gill relates in his book Here at The New Yorker that at one point in the early 1940s, the quality of the artwork submitted to the magazine seemed to improve. It later was found out that the office boy (a teenaged Truman Capote) had been acting as a volunteer art editor, dropping pieces he did not like down the far end of his desk.

Several of the magazine's cartoons have reached a higher plateau of fame. One 1928 cartoon drawn by Carl Rose and captioned by E. B. White shows a mother telling her daughter, "It's broccoli, dear." The daughter responds, "I say it's spinach and I say the hell with it." The phrase "I say it's spinach" entered the vernacular, and three years later, the Broadway musical Face the Music included Irving Berlin's song "I Say It's Spinach (And the Hell with It)". The catchphrase "back to the drawing board" originated with the 1941 Peter Arno cartoon showing an engineer walking away from a crashed plane, saying, "Well, back to the old drawing board."

The most reprinted is Peter Steiner's 1993 drawing of two dogs at a computer, with one saying, "On the Internet, nobody knows you're a dog". According to Mankoff, Steiner and the magazine have split more than $100,000 in fees paid for the licensing and reprinting of this single cartoon, with more than half going to Steiner.

Over seven decades, many hardcover compilations of New Yorker cartoons have been published, and in 2004, Mankoff edited The Complete Cartoons of The New Yorker, a 656-page collection with 2,004 of the magazine's best cartoons published during 80 years, plus a double CD set with all 68,647 cartoons ever published in the magazine. This features a search function allowing readers to search for cartoons by cartoonist's name or year of publication. The newer group of cartoonists in recent years includes Pat Byrnes, J. C. Duffy, Liana Finck, Emily Flake, Robert Leighton, Michael Maslin, Julia Suits, and P. C. Vey. Will McPhail cited his beginnings as "just ripping off Calvin and Hobbes, Bill Watterson, and doing little dot eyes." The notion that some New Yorker cartoons have punchlines so oblique as to be impenetrable became a subplot in the Seinfeld episode "The Cartoon", as well as a playful jab in The Simpsons episode "The Sweetest Apu".