Jackie spent large portions of her time in New York to be with her children. As the years went by, the Onassis marriage was rumored to be a difficult one, and the couple began to spend most of their time apart. Aristotle Onassis died in 1975 and, widowed for a second time, Jackie returned permanently to New York. In 1975 she began working as a book editor at Viking amidst much speculation about whether or not she would be able to get along with her fellow workers, or if her very presence would make it difficult for the office to function. She quickly adapted to her new job and remained at Viking until she resigned in 1977. In 1978 she took a job as an associate editor at Doubleday Publishing where she continued to work into the 1990s. In 1982 she was promoted to full editor and later became a senior editor. In 1994 Jackie Kennedy made public the information that she was being treated for non-Hodgkin's lymphoma and that her condition was responding well to therapy. However, the disease proved fatal on May 19, 1994. She is buried next to John F. Kennedy in Arlington National Cemetary.

Her daughter Caroline is a mother and lawyer. Her son John was the editor in chief of the political magazine George until his death in a plane crash in 1999. John Jr.'s wife, Caroline Bessette-Kennedy, and her sister, Lauren Bessette, also perished in the crash. .