Jackson was born Jesse Louis Burns in Greenville, South Carolina to Helen Burns. Helen Burns was a single mother, aged 16, when he was born. His biological father, Noah Louis Robinson, a former professional boxer and a prominent figure in the black community, was married to another woman when Jesse was born. He was not involved in his son's life. In 1943, two years after Jesse's birth, his mother married Charles Henry Jackson who would adopt Jesse 14 years later. Jesse went on to take the surname of his stepfather.

Jackson attended Sterling High School, a segregated high school in Greenville, where he was an outstanding student-athlete. Upon graduating in 1959, he rejected a contract from a professional baseball team so that he could attend the racially integrated University of Illinois on a football scholarship. However, one year later, Jackson transferred to North Carolina Agricultural and Technical State University (A&T) located in Greensboro, North Carolina. There are differing accounts for the reasons behind this transfer. Jackson claims that the change was based on the school's racial biases which included his being unable to play as a quarterback despite being a star quarterback at his high school as well as being demoted by his speech professor as an alternate in a public speaking competition team despite the support of his teammates who elected him a place on the team for his superior abilities. ESPN.com reports a different story, however. Claims of racial discrimination on the football team may be exaggerated because Illinois's starting quarterback that year was an African American. In addition, Jackson left Illinois at the end of his second semester after being placed on academic probation. Following his graduation from A&T, Jackson attended the Chicago Theological Seminary with the intent of becoming a minister, but dropped out in 1966 to focus full-time on the civil rights movement. (He would be ordained in 1968, without a theological degree, and was awarded an honorary theological doctorate from Chicago in 1990.)

While Jackson was initially critical of the " Third Way" or more moderate policies of Bill Clinton, he became a key ally in gaining African American support for Clinton and eventually became a close advisor and friend of the Clinton family. Clinton awarded Jackson the Medal of Freedom, the nation's highest honor bestowed on civilians. His son, Jesse Jackson, Jr., also emerged as a political figure, becoming a member of the United States House of Representatives from Illinois. Jackson is also known as a passionate orator, in the tradition of Southern U.S. and African American Protestant preaching. In 2003, Jackson surprised many observers by declining to endorse the campaigns of either the Reverend Al Sharpton or former Senator Carol Moseley Braun, the two African American candidates, in the race for the Democratic Party's 2004 presidential nomination. Instead, Jackson remained largely silent about his preference in the race until late in the primary season, when he allowed Democratic Representative Dennis Kucinich of Ohio, another presidential candidate, to speak at a Rainbow/PUSH forum on March 31, 2004. Although he did not explicitly voice an endorsement of Rep. Kucinich, Jackson described Kucinich as "assuming the burden of saying 'you make the most sense, but you can't win.'" He also writes for The Progressive Populist.

In 2005, he was enlisted as part of the United Kingdom's "Operation Black Vote", a campaign to encourage more of Britain's ethnic minorities to vote in political elections ahead of the May 2005 General Election. Also in early 2005, Jackson visited the parents of Terri Schiavo and their supporters; he supported their unsuccessful bid to keep the disabled Florida woman alive. In March 2006, Crystal Gail Mangum had accused three men of the Duke University Men's Lacrosse team of raping her. Jackson had agreed to pay the rest of her college tuition regardless of the outcome of the case. The case against the Duke Lacrosse team was later thrown out after all charges were dropped against the three lacrosse players.

Jackson took a key role in the scandal caused by comedic actor Michael Richards' racially charged comments in November 2006. Richards called Jackson a few days after the incident to apologize; Jackson accepted Richards' apology and met with him publicly as a means of resolving the situation. Jackson also joined black leaders in a call for the elimination of the "N-word" throughout the entertainment industry.