Born on the South Side of Chicago in the Grand Crossing neighborhood, Comer graduated from the Paul Revere Elementary School in 1942 and Hyde Park High School in 1946. From 1950 to 1960, he worked as a copywriter at Young & Rubicam in Chicago. After quitting, he traveled around Europe for a year, and then, having been an avid sailor from childhood, he began his own business supplying sailing equipment.
In the Spring of 1963 Comer founded Lands' End, along with his close friend Robert Halperin, Richard Stearns, and two of Stearns' employees. They started it originally as a retailer of sailing supplies and equipment (based on a mail order equipment business begun a year earlier). Comer served as president through 1990 (including following Lands' End's registration as a public company), when he stepped down from active management. He remained a major shareholder until Lands' End was acquired by Sears in 2002.
Comer was a long-time philanthropist, donating money to causes including children's health care, education and the study of global climate change. He opened the Gary Comer Youth Center which houses among other things Gary Comer College Prep, a campus of the Noble Network of Charter Schools. Comer was a major contributor to the University of Chicago, providing more than $84 million in donations leading to the establishment and expansion of the Comer Children's Hospital at the University of Chicago.
Comer and Francie (ne Ceraulo) were married from 1962 until his death. They had two children.