In his home town of Saratoga, New York, Solomon Northup, a free negro who was a skilled carpenter and violinist, was approached by two circus promoters. They offered him a brief, high-paying job as a musician with their traveling circus. Without informing his wife, who was away at work in a nearby town, he traveled with the strangers to downstate New York and Washington, D.C. Soon after arriving in the capital, he awoke to find himself drugged, bound, and in the cell of a slave pen. When Northup asserted his rights as a free man, he was beaten and warned never again to mention his free life in New York.

Transported by ship to New Orleans, Northup and other enslaved blacks contracted smallpox and one died. In transit, Northup implored a sympathetic sailor to send a letter to his family. The letter arrived safely, but, lacking knowledge of his final destination, Northup's family was unable to effect his rescue.

Northup's first owner was William Prince Ford, who ran a lumber mill on a bayou of the Red River. Northup subsequently had several other owners, less humane than Ford, during his twelve-year bondage. At times, his carpentry and other skills contributed to his being treated relatively well; but he also suffered extreme cruelty. On two occasions, he was attacked by a white man he was leased to, John Tibeats, and defended himself, for which he suffered severe reprisals. After about two years of enslavement, he was sold to Edwin Epps, a notoriously cruel cotton planter. Epps held Northup enslaved for 10 years, during which time he assigned the New Yorker to various roles from cotton picker, to hauler to driver, which required Northup to oversee the work of fellow slaves and punish them for undesirable behavior. While on Epps' plantation, Northup became friends with a slave girl named Patsey, who Northup writes about briefly in the book.