She was born in Chicago, Illinois, the daughter of Edwin John Howell, Jr. (1897–1946), a Chicago firefighter, and Della Murray (1902–1960). Her sister is Isabelle Howell (born 1924). The parents were dysfunctional and unhappy and paid only sporadic attention to the children before divorcing in 1927. The children were then sent on train by themselves to live with their paternal grandparents in the Los Angeles suburb of Alhambra, California. The sisters endured harsh treatment from the grandparents and Dorothy left home at age 14, working as a nanny. After Dorothy graduated from Alhambra High School in 1937, she moved to Chicago for a failed reunion with her mother. Subsequently, she moved into her own apartment there and took office jobs to support herself.

While applying for a job as a clerk typist at a textile company, Dorothy met traveling salesman Hugh Ellsworth Rodham, eight years her senior, in 1937. After a lengthy courtship, they married in early 1942. She became a full-time homemaker, raising three children, Hillary, Hugh and Tony in suburban Park Ridge, Illinois. She encouraged Hillary to have a love for learning and to pursue an education and a career, though she had never done so herself. In contrast to her husband's staunch Republican views, Dorothy Rodham was, as her daughter later wrote, "basically a Democrat, although she kept it quiet in Republican Park Ridge."

In 1987, Dorothy and her husband moved to Little Rock, Arkansas, to be closer to their daughter and granddaughter, Chelsea. An excellent student as a youth, Dorothy Rodham now took college courses in subjects such as psychology, logic, and child development, although she never graduated.

Hugh Rodham died in 1993. By the 2000s, Dorothy was living in her daughter's large Whitehaven house in Kalorama, Washington, D.C. Dorothy Rodham is active but values her privacy and almost never speaks to the media, though in December 2007 she made a rare public appearance in Iowa to campaign for her daughter's presidential nomination bid, and later appeared in a Clinton campaign television advertisement.

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