Ross was elected governor of Wyoming in 1924, succeeding her husband, incumbent Democrat William Bradford Ross, who died just prior to the election. After narrowly losing to a Republican candidate for governor in 1926, Ross was appointed vice chairman of the Democratic National Committee.

In 1933 President Franklin D. Roosevelt named Ross director of the U.S. Mint, making her one of the first women to hold a federal post of that importance. During her 20-year term the mint introduced the Roosevelt dime, the Jefferson nickel, and the steel penny, the latter an emergency measure during World War II.

Ross won the distinction of becoming the first woman governor by a small margin; Miriam Ferguson was inaugurated governor of Texas just 16 days later.