Addams graduated from Rockford Female Seminary in Illinois in 1881 and was granted a degree the following year when the institution became Rockford College. Following the death of her father in 1881, her own health problems, and an unhappy year at the Woman's Medical College, Philadelphia, she was an invalid for two years. During neither subsequent travel in Europe in 1883–85 nor her stay in Baltimore, Maryland, in 1885–87 did she find a vocation.

In 1887–88 Addams returned to Europe with a Rockford classmate, Ellen Gates Starr (Starr, Ellen Gates). On a visit to the Toynbee Hall settlement house (founded 1884) in the Whitechapel industrial district in London, Addams's vague leanings toward reform work crystallized. Upon returning to the United States, she and Starr determined to create something like Toynbee Hall. In a working-class immigrant district in Chicago, they acquired a large vacant residence built by Charles Hull in 1856, and, calling it Hull House, they moved into it on September 18, 1889. Eventually the settlement included 13 buildings and a playground, as well as a camp near Lake Geneva, Wisconsin. Many prominent social workers and reformers—Julia Lathrop (Lathrop, Julia Clifford), Florence Kelley (Kelley, Florence), and Grace (Abbott, Grace) and Edith Abbott (Abbott, Edith)—came to live at Hull House, as did others who continued to make their living in business or the arts while helping Addams in settlement activities.

Among the facilities at Hull House were a day nursery, a gymnasium, a community kitchen, and a boarding club for working girls. Hull House offered college-level courses in various subjects, furnished training in art, music, and crafts such as bookbinding, and sponsored one of the earliest little-theatre groups, the Hull House Players. In addition to making available services and cultural opportunities for the largely immigrant population of the neighbourhood, Hull House afforded an opportunity for young social workers to acquire training.

Addams worked with labour as well as other reform groups toward goals including the first juvenile-court law, tenement-house regulation, an eight-hour working day for women, factory inspection, and workers' compensation. She strove in addition for justice for immigrants and blacks, advocated research aimed at determining the causes of poverty and crime, and supported woman suffrage. In 1910 she became the first woman president of the National Conference of Social Work, and in 1912 she played an active part in the Progressive Party's presidential campaign for Theodore Roosevelt. At The Hague in 1915 she served as chairman of the International Congress of Women, following which was established the Women's International League for Peace and Freedom. She was also involved in the founding of the American Civil Liberties Union in 1920. In 1931 she was a cowinner of the Nobel Prize for Peace.

The establishment of the Chicago campus of the University of Illinois in 1963 forced the Hull House Association to relocate its headquarters. The majority of its original buildings were demolished, but the Hull residence itself was preserved as a monument to Jane Addams.

Among Addams's books are Democracy and Social Ethics (1902), Newer Ideals of Peace (1907), Twenty Years at Hull-House (1910), and The Second Twenty Years at Hull-House (1930).