She earned a Ph.D. in Harvard Mathematics, was a postdoctoral fellow in MIT's Department of Mathematics, and a professor at Barnard College, where she published a series of research papers on arithmetic algebraic geometry. She then switched to the private sector, working as Expert in quantitative information analysis and management for the hedge fund DE Shaw in the midst of the credit crisis, and then for RiskMetrics, a risk software company that assesses risk for hedge fund and bank holdings. In the world of finance, O'Neil became involved with the Occupy Wall Street movement, participating in her Alternative Banking Group. She left finance definitively in 2011 and began working as a data scientist in the New York startup sector, creating models that predicted people's purchases and clicks. She is a weekly guest on the Slate Money podcast. She is co-author (with Rachel Schutt) of Doing Data Science: Straight Talk from the Frontline. He also wrote the Being a Data Skeptic ebook.

His book Weapons of Mathematical Destruction was published in the United States in 2016 and was nominated for the 2016 National Book Award in the non-fiction category. Cathy maintains the blog mathbabe.org, where she opines on everything quantitative. In it he hopes to find a better answer to the question: "What can a non-academic mathematician do to make the world a better place?"