Ramona Fradon was born in Chicago and moved to New York when she was five. She grew up on the outskirts of New York City in Westchester County. Her father, Peter Dom, was a well known commercial lettering man and designed logos for Elizabeth Arden, Camel, and Lord & Taylor. Fradon also had an older brother and uncle in the lettering business. Her brother worked as a technician for the Air Corps overseas and eventually died of alcoholism. Her mother fell ill and died in 1952. She never read comic books growing up but she had a love for newspaper strips. Fradon's father was the one that encouraged her to go to art school.
Ramona Fradon entered cartooning just after graduating from the Parsons School of Design. Soon after she left art school, she married her husband, New Yorker cartoonist Dana Fradon, who encouraged her to try cartooning. Comic-book letterer George Ward, a friend of her husband, asked her for samples of her artwork to pitch for job openings. She landed her first assignment on the DC Comics with work on Shining Knight. Her first regular assignment was illustrating an Adventure Comics backup feature starring Aquaman. This included a revamping of the character for the Silver Age of Comics in Adventure Comics #260 (May 1959). Alongside said revamp, she and writer Robert Bernstein co-created the sidekick Aqualad in Adventure Comics #269 (February 1960).
Following her time with Aquaman, Fradon returned to co-create Metamorpho. She drew the characters to 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. She later commented, "I think [writer Bob Haney and I] both felt that Metamorpho was our baby. I never had an experience like I had working with Bob Haney on Metamorpho. It was like our minds were in perfect synch ... it was one of those wonderful collaborations that doesn't happen very often." 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.

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