He was the son of Wallace Edwards, a textile-mill worker, and Catherine (“Bobbie”) Wade Edwards, a textile worker and later postal worker. He grew up in the mill town of Robbins, North Carolina. The first in his family to attend college, Edwards received a bachelor's degree in textile management from North Carolina State University in 1974 and a law degree from the University of North Carolina at Chapel Hill in 1977. That year he also married a fellow law student, Elizabeth Anania. Edwards became a successful attorney, first in Nashville, Tennessee, and then in Raleigh, North Carolina, winning multimillion-dollar verdicts in personal-injury lawsuits. The death of his 16-year-old son, Wade, in an automobile accident in 1996 helped to impel Edwards into public service and philanthropy, and in 1998 he was elected to the U.S. Senate from North Carolina.

As a senator, Edwards cosponsored a patients' bill of rights and supported education reform. As a member of the Senate Select Committee on Intelligence, he proposed legislation on strengthening homeland security. Seeking the Democratic presidential nomination in 2004, Edwards struck a populist tone, with charismatic stump speeches that evoked his modest upbringing in Robbins. Though Edwards's presidential bid was unsuccessful, John Kerry, the party's eventual nominee, chose him as his running mate. The pair was narrowly defeated in the November elections by incumbent President George W. Bush (Bush, George W.) and Vice President Dick Cheney (Cheney, Dick).

Edwards subsequently devoted much of his time to antipoverty efforts, becoming director of the newly created Center on Poverty, Work, and Opportunity at the University of North Carolina in 2005. The following year he announced that he would seek the Democratic Party's presidential nomination in 2008. Edwards's bid for the presidency got off to an inauspicious start, as he finished second in the Iowa caucus, third in the New Hampshire primary, and third in the South Carolina primary (his native state) in January 2008. In late January he withdrew from the race.