Friedman, 98, was believed to have died of heart failure, the Indianapolis Star reported.
While her husband, who won a Nobel Prize for economics, was better known as an advocate of free markets, Friedman worked with him on his books and on other projects. The couple founded the Indianapolis-based Rose and Milton Friedman Foundation, which advocates for school choice and vouchers, in 1996.
Friedman helped her husband write "Free to Choose" and many of his other works.
Born in a small village in Russia, Friedman was brought to the United States as a baby. Official records of her birth were lost but she believed she was born in December 1910, the newspaper said.
She met her husband in 1932 at the University of Chicago when they were seated next to each other by alphabetical order in a graduate class, and they married in 1938.
Milton Friedman died in November 2006.
"She will be remembered both as a talented economist and an influential advocate of freedom," the foundation said.
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