Ellen was the oldest of seven children of Samuel Axson, a Presbyterian minister, and Margaret Hoyt Axson. During the birth of their last child in 1881, when Ellen was 21 years old, Margaret Axson died. The subsequent mental breakdown of Ellen's father and his death in 1884 left her the head of the family.

As soon as she could place her younger siblings with relatives in Georgia, Ellen took her small inheritance and moved to New York City to study painting at the Art Students League, an unusually brave step for a young woman at that time. Her move is even more surprising considering that she had already met Woodrow Wilson (in 1883), and he had proposed marriage. She could have remained in Georgia while he completed his doctorate, but she chose a more independent course.

Ellen and Woodrow married on June 24, 1885, at her paternal grandfather's home in Savannah, Georgia, and they moved to Bryn Mawr, Pennsylvania, where he took a job as an associate professor of history and political economy at Bryn Mawr College. Although much of her time was spent caring for her three daughters, born between 1886 and 1889, and her siblings, she managed to study German, in order to translate for her husband, and to take a course in home economics. Woodrow's tenure as president of Princeton University (1902–10) allowed her to polish her household management and hostess skills, which later served her in the White House, and his two years as governor of New Jersey (1910–12) helped her to develop a public persona. She continued to paint portraits and landscapes and exhibited her work, for which she received excellent reviews in juried competitions, under the name E.A. Wilson, after her husband became famous.

Ellen served only 17 months as first lady, and for much of the time she was ill. Nevertheless, she made the time count. Although she took no public stand on woman suffrage (which her husband still opposed), she served as honorary president of the National Civic Foundation, advocated better working conditions for women and children, and lobbied vigorously to improve the housing conditions of African Americans living in the alleys of Washington. Her efforts resulted in a federal bill setting minimum housing standards in the District of Columbia, which was passed by both the House and the Senate in August 1914, as she lay dying in the White House of Bright disease. Never before had a president's wife been so closely associated with legislation.

Ellen Wilson was buried in Rome, Georgia, near the graves of her parents. As her biographer Frances Saunders has noted, she showed how it was possible for the first lady to combine political work on behalf of social causes with her more traditional domestic duties.