Work on the school began in February 1931, and was specifically constructed to accommodate the increasing population of Phillips High School. Construction was delayed for financial reasons, and was completed with a public works grant. The school opened on February 4, 1935, and was called New Wendell Phillips High School. New Phillips was a part of a five high school expansion that included Lane Tech High School, Steinmetz High School, Senn High School, and . The building was designed by Paul Gerhardt, Sr., an architect for the Chicago Board of Education.
On April 25, 1936, the school's name was changed to honor Jean Baptiste Point DuSable, the first non-native to settle the area; however there was a delay in implementing the name, as the exact spelling was in dispute. During the 1940s on thru the 1960s, DuSable enrollment was more than 4,000 which prompted two graduation ceremonies (spring and summer). During this period, DuSable became notable for its music program: Captain Walter Dyett was the longtime music instructor at the school. By the late 1950s, DuSable was surrounded by the Robert Taylor Homes, a Chicago Housing Authority public housing project and approximately 80% of the student population were residents. The Robert Taylor Homes project was demolished in stages between 1998 and 2007.
With the demolition of the Robert Taylor Homes, student enrolment at DuSable had substantially declined. Because of this, in 2003, Chicago Public Schools decided to phase out DuSable: the history of poor academic performance was also a factor. In 2005, three schools were opened in the building as a part of the Renaissance 2010 program. The three new schools: Bronzeville Scholastic Institute, Daniel Hale Williams School of Medicine and DuSable Leadership Academy were created by DuSable staff members. The DuSable Leadership Academy which was a part of the Betty Shabazz International Charter School was phased out due to poor academic performance and closed after the 2015–16 school year.