Jesse adopted the name of his stepfather, Charles Jackson, at about age 15. A good student in high school, Jesse was elected class president and later attended the University of Illinois (1959–60) on a football scholarship. He then transferred to the predominantly black Agricultural and Technical College of North Carolina in Greensboro and received a B.A. in sociology (1964). He moved to Chicago in 1966, did graduate work at the Chicago Theological Seminary, and was ordained a Baptist minister in 1968.

Jackson began traveling widely in the late 1970s to mediate or spotlight international problems and disputes. In 1979 he visited South Africa, where he spoke out against apartheid, and he later journeyed to the strife-ridden Middle East and campaigned to give Palestinians their own state. While some observers and government officials frowned on his diplomatic missions as meddlesome and self-aggrandizing, Jackson nonetheless won praise for negotiating the release of U.S. soldiers and civilians around the world, including in Syria (1984), Iraq (1990), and Yugoslavia (1999).

In the 1980s Jackson became a leading national spokesman and advocate for African Americans. His voter-registration drive was a key factor in the election of Chicago's first African American mayor, Harold Washington (Washington, Harold), in April 1983. The following year Jackson ran for the Democratic presidential nomination. During the campaign he drew criticism for his relationship with Louis Farrakhan (Farrakhan, Louis) of the Nation of Islam and for making a disparaging remark about New York's Jewish community; Jackson later apologized for his comments and distanced himself from Farrakhan. In what was then the strongest showing ever by an African American candidate, Jackson placed third in the primary voting. In 1988 he staged another bid for the Democratic nomination and came in second to the party's eventual nominee, Michael Dukakis (Dukakis, Michael S.). Jackson's increasing influence within the Democratic Party ensured that African American issues were an important part of the party's platform. Jackson, a dynamic orator, made memorable speeches at later Democratic conventions but declined to run again for the presidency.

In 1989 Jackson took residency in Washington, D.C., and in 1990, when the Washington City Council created two unpaid offices of “statehood senator”—popularly called “shadow senator”—to lobby the U.S. Congress for statehood for the District of Columbia, Jackson won election to one of the posts, his first elective office. In 1997 President Bill Clinton (Clinton, Bill) named him a special envoy to Africa, where he traveled to promote human rights and democracy. That year Jackson also founded the Wall Street Project, which sought to increase minority opportunities in corporate America.

During the impeachment hearings against Clinton in 1998, Jackson counseled the president, and in 2000 Clinton awarded him the Presidential Medal of Freedom. That year Jackson also received a Master of Divinity degree from the Chicago Theological Seminary. The following year, however, he became embroiled in controversy when it was revealed that he had fathered a child out of wedlock. Jackson continued his social activism, giving lectures and leading protests. His books include Straight from the Heart (1987; ed. by Roger D. Hatch and Frank E. Watkins) and Legal Lynching: Racism, Injustice, and the Death Penalty (1995). His son Jesse Jackson, Jr., was elected to the U.S. Congress in 1995.