It was founded in 1961 by Margaret Taylor-Burroughs, her husband Charles Burroughs, Gerard Lew, Eugene Feldman, Bernard Goss, Marian M. Hadley, and others.

[3][5][6] In 1968, the museum was renamed for Jean Baptiste Point du Sable, a fur trader of black African ancestry and the first non-Native-American permanent settler in Chicago.

[7][8] During the 1960s, the museum and the South Side Community Art Center, which was located across the street, founded in 1941 by Taylor-Burroughs and dedicated by Eleanor Roosevelt,[9] formed an African-American cultural corridor.

[7] This original museum site had previously been a social club [10] and boarding house for African-American railroad workers and is now listed as a Chicago Landmark and on the National Register of Historic Places.

[7][11] The DuSable Black History Museum quickly filled a void caused by limited cultural resources then available to African Americans in Chicago.

[15] This willingness to adapt has allowed it to survive while other museums faltered due to a weakening economy and decreased public support.

It has United States slavery-era relics, nineteenth- and twentieth-century artifacts, and archival materials, including the diaries of sea explorer Captain Harry Dean.

The museum also owns prints and drawings by Henry O. Tanner, Richmond Barthé, and Romare Bearden, and has an extensive collection of books and records pertaining to African and African-American history and culture.

[7][24] The original north entrance contains the main lobby of the museum and features the Thomas Miller mosaics, which honor the institution's founders.