Simon was raised in Rochester, New York, the son of a tailor. He attended Benjamin Franklin High School, where he was art director for the school newspaper and the yearbook ... earning his first professional fee as an artist when two universities each paid $10 publication rights for his art deco, tempera splash pages for the yearbook sections. Upon graduation in 1932, Simon was hired by Rochester Journal American art director Adolph Edler as an assistant, replacing Simon's future comics colleague Al Liederman, who had quit. Two years later, Simon took an art job at the Syracuse Herald in Syracuse, New York, and shortly thereafter succeeded Liederman as art director of the Syracuse Journal American. This short-lived job ended when the Newhouse chain bought and consolidated the three local newspapers.

Venturing to New York City, Simon freelanced for Paramount Pictures retouching the movie studio's publicity photos, and for McFadden Publications, doing illustrations for True Story and other magazines. Sometime afterward, his boss, art director Harlan Crandall, recommended Simon to Lloyd Jacquet, head of comic-book packager Funnies, Inc.. That day, Simon received his first comics assignment, a seven-page Western. Four days later, Jacquet asked Simon, at the behest of Timely Comics publisher Martin Goodman to create a flaming superhero like Timely's successful character The Human Torch. From this came Simon's first comic-book hero, the Fiery Mask.

During this time, Simon met Fox Feature Syndicate comics artist Jack Kirby, with whom he would soon have a storied collaboration lasting a decade-and-a-half. Speaking at a 1998 Comic-Con International panel in San Diego, California, Simon recounted the meeting:

with the comic book industry beset by self-imposed censorship, negative publicity, and a slump in sales. Simon turned primarily to [[advertising]] and [[commercial art]], while dipping back into comics on occasion. He created, edited and produced material for the humor magazine ''Sick'', a competitor of ''[[Mad (magazine)|Mad]]'' magazine, for over a decade. The Simon & Kirby team reunited briefly in 1959 with Simon writing and collaborating on art for [[Archie Comics]], where the duo updated the superhero the [[The Shield (Archie Comics)|Shield]] in the two-issue ''The Double Life of Private Strong'' (June-Aug. 1959), and Simon created the superhero [[The Fly (Archie Comics)|Fly]]; they went on to collaborate on the first two issues of ''The Adventures of the Fly'' (Aug.-Sept. 1959) and Simon and other artists including [[Al Williamson]], [[Jack Davis (cartoonist)|Jack Davis]], [[Carl Burgos]] and others did four issues before Simon moved on. Simon & Kirby again reteamed for [[Harvey Comics]] in 1966, updating Fighting American for a single issue (Oct. 1966). Simon, as owner, packager, and editor, also helped launch Harvey's original superhero line, with ''Unearthly Spectaculars'' #1-3 (Oct. 1965 - March 1967) and ''Double-Dare Adventures'' #1-2 (Dec. 1966 - March 1967), the latter of which introduced the influential writer-artist [[Jim Steranko]] to comics.

In 1968, Simon created the two-issue DC Comics series Brother Power the Geek, about a mannequin given a semblance of life who wanders philosophically through 1960s hippie culture; Al Bare provided some of the art. Simon and artist Jerry Grandenetti then created DC's four-issue Prez (Sept. 1973 - March 1974), about America's first teen-age president.

Simon & Kirby teamed one last time later that year, with Simon writing the first issue (Winter 1974) of a six-issue new incarnation of the Sandman. Simon and Grandenetti then created the Boy Millionaires in the DC try-out series 1st Issue Special #2 (May 1975), and the freakish Outsiders in 1st Issue Special #10 (Jan. 1976).

In the 2000s, Simon turned to painting and marketing reproductions of his early comic book covers. Simon in 2007 appeared in various news media in response to Marvel Comics announced "death" of Captain America in Captain America vol. 5, #25 (March 2007), stating, "It's a hell of a time for him to go. We really need him now".