Frances Hamilton Arnold was born in Edgewood, a suburb of Pittsburgh, Pennsylvania. Even from a young age, she displayed a strong independent spirit, setting the stage for her future unconventional approach to science.

Demonstrating a proactive nature, Arnold hitchhiked across the US and worked in a pizza parlor to fund her independent endeavors. She also engaged in protests against the Vietnam War and nuclear power, demonstrating her early commitment to social and environmental issues which would later influence her scientific pursuits.