In 1900, Joe, Frank, and their sister Mary moved to New York City, then the center of the US commercial art, advertising and publishing industries. During the next decade, both brothers began lucrative long-term working relationships with apparel manufactures including Interwoven Socks, Hartmarx, B. Kuppenheimer & Co., and Cluett Peabody & Company. The latter resulted in Leyendecker's most important commission when he was hired to develop a series of images of the Arrow brand of shirt collars. Leyendecker's Arrow Collar Man, as well as the images he later created for Kuppenheimer Suits and Interwoven Socks, came to define the fashionable American male during the early decades of the twentieth century Leyendecker often used his favorite model and life partner, Charles Beach (1881–1954).^[

Another important commission for Leyendecker was from Kellogg's, the breakfast food manufacturer. As part of a major advertising campaign, he created a series of twenty "Kellogg's Kids" to promote Kellogg's Corn Flakes.

In 1914, the Leyendeckers, accompanied by Charles Beach, moved into a large home and art studio in New Rochelle, New York, where J. C. would reside for the remainder of his life. During the first World War, in addition to his many commissions for magazine covers and men's fashion advertisements, J. C. also painted recruitment posters for the United States military and the war effort.

The 1920s were in many ways the apex of Leyendecker's career, with some of his most recognizable work being completed during this time. Modern advertising had come into its own, with Leyendecker widely regarded as among the preeminent American commercial artists. This popularity extended beyond the commercial, and into Leyendecker's personal life, where he and Charles Beach hosted large galas attended by people of consequence from all sectors. The parties they hosted at their New Rochelle home/studio were important social and celebrity making events.

As the 1920s marked the apex of J. C. Leyendecker's career, so the 1930s marked the beginning of its decline. Around 1930–31, Cluett, Peabody, & Co. ceased using Leyendecker's illustrations in its advertisements for shirts and ties as the collar industry seriously declined after 1921. During this time, the always shy Leyendecker became more and more reclusive, rarely speaking with people outside of his sister Mary Augusta and Charles (Frank had died in 1924 as a result of an addiction-riddled lifestyle). Perhaps in reaction to his pervasive popularity in the previous decade, or as a result of the new economic reality following the Wall Street Crash of 1929, the number of commissions Leyendecker received steadily declined. In 1936, the editor at the Saturday Evening Post for all of Leyendecker's career up to that point, George Horace Lorimer, retired, and was replaced by Wesley Winans Stout (1937–1942) and then Ben Hibbs (1942–1962), both of whom rarely commissioned Leyendecker to illustrate covers.

Leyendecker's last cover for the Saturday Evening Post was of a New Year Baby for January 2, 1943, thus ending the artist's most lucrative and celebrated string of commissions. New commissions continued to filter in, but slowly. Among the most prominent were posters for the United States Department of War, in which Leyendecker depicted commanding officers of the armed forces encouraging the purchases of bonds to support the nation's efforts in World War II.