Ramona Fradon entered cartooning just after graduating from the Parsons School of Design. Comic-book letterer George Ward, a friend of her husband (New Yorker cartoonist Dana Fradon), asked her for samples of her artwork to pitch for job openings. She landed her first assignment on the DC Comics feature "Shining Knight". Her first regular assignment was illustrating an Adventure Comics backup feature starring Aquaman. She and writer Robert Bernstein co-created the sidekick Aqualad in Adventure Comics #269 (Feb. 1960).
Following her time with Aquaman, Fradon returned to co-create Metamorpho. She drew the character's two try-out appearances in The Brave and the Bold and the first four issues of the eponymous series and returned briefly to design a few covers for the title. Fradon drew The Brave and the Bold #59 (April–May 1965), a Batman/Green Lantern team-up, the first time that series featured Batman teaming with another DC superhero.
From 1965 to 1972, Fradon left comics to raise her daughter. In 1972, she returned to DC where later in the decade she would draw Plastic Man, Freedom Fighters, and Super Friends which she penciled for almost its entire run. She also worked for Marvel Comics during this period, but left after only two assignments: a fill-in issue of Fantastic Four and the never-published fifth issue of The Cat. Fradon recounted:
First of all, I was really rusty. And [on The Cat #5] I was totally confounded by not drawing from a script. They gave me this one paragraph and said go draw this 17-page story. I don’t think I did my best work by any means. I think I had a script on Fantastic Four, but I just don’t think they were satisfied with my work. Then I went back to DC and started doing mysteries with Joe Orlando. I really had a lot of fun doing that. It suited my style, I think.
In 1980, Dale Messick retired from drawing the newspaper strip Brenda Starr, Reporter, and Fradon became the artist for it until her own retirement in 1995.
She contributed pencils to the 2010 graphic novel The Adventures of Unemployed Man, the 2012 graphic novel The Dinosaur That Got Tired of Being Extinct, and the collection The Art of Ramona Fradon.
Based on an idea by DC editor George Kashdan and co-created by Bob Haney and Fradon, the character Metamorpho first appeared in The Brave and the Bold #57 and 58 in January and March 1965 before headlining a 17-issue run of the character's self-titled series from August 1965 through March 1968.
Kashdan's concept involved a character made up of four elements who could change into different chemical compounds. Haney fleshed out the idea with a "deliciously overdrawn" cast.
Kashdan, Haney, and Fradon worked together to create Metamorpho's look:
He wasn’t your average superhero so capes and masks didn’t suit him. I tried a lot of those and finally decided that since he was always changing his shape, clothes would get in his way. So I drew him in tights, with a body made up of four different colors and textures that were supposed to indicate the four elements.
Fradon enjoyed her collaboration with Haney because “his goofy stories gave me ideas about how the characters should look and act, and my goofy pictures gave him new ideas.” Metamorpho allowed Fradon to use an exaggerated drawing style which suited her better than the traditional approach to superhero illustration. Feeling "like a fish out of water" in the male-dominated superhero field, she reflected on her style in a 1988 interview:
[Trina Robbins] made the observation that most women tend to have a more open style, use less shadow, and work in bigger open patterns. I think that’s probably true—at least I always did (work in that style). I thought that was a big failing of mine, that I couldn’t emulate that kind of photographic reproduction style. When I read that this seemed to be a characteristic of women cartoonists, it made me feel a bit better about it. […] Something that always jarred my eyes is to see the kind of heaviness and ugliness about most comic art. There’s not much sweetness to it. It’s the tradition, and I don’t think it has anything to do with the individual artists. It’s just the tradition…the look. That always troubled me.
Fradon was inducted into the Will Eisner Comic Book Hall of Fame in 2006.