The story begins in fictional St. Petersburg, Missouri (based on the actual town of Hannibal, Missouri), on the shore of the Mississippi River "forty to fifty years ago" (the novel having been published in 1884). Huckleberry "Huck" Finn (the protagonist and first-person narrator) and his friend, Thomas "Tom" Sawyer, have each come into a considerable sum of money as a result of their earlier adventures (detailed in The Adventures of Tom Sawyer). Huck explains how he is placed under the guardianship of the Widow Douglas, who, together with her stringent sister, Miss Watson, are attempting to "sivilize" him and teach him religion. Huck finds civilized life confining. His spirits are raised when Tom Sawyer helps him to slip past Miss Watson's slave, Jim, so he can meet up with Tom's gang of self-proclaimed "robbers". Just as the gang's activities begin to bore Huck, his shiftless father, "Pap", an abusive alcoholic, suddenly reappears. Huck, who knows his father will spend the money on alcohol, is successful at keeping his fortune out of his father's hands. Pap, however, kidnaps Huck and takes him out of town.

In Illinois, Jackson's Island and while going Downriver
Pap forcibly moves Huck to an abandoned cabin in the woods along the Illinois shoreline. To evade further violence and escape imprisonment, Huck elaborately fakes his own murder, steals his father's provisions, and sets off downriver in a 13/14-foot long canoe he finds drifting downstream. Soon, he settles comfortably on Jackson's Island, where he reunites with Jim, Miss Watson's slave. Jim has also run away after he overheard Miss Watson planning to sell him "down the river" to presumably more brutal owners. Jim plans to make his way to the town of Cairo in Illinois, a free state, so that he can later buy the rest of his enslaved family's freedom. At first, Huck is conflicted about the sin and crime of supporting a runaway slave, but as the two talk in-depth and bond over their mutually held superstitions, Huck emotionally connects with Jim, who increasingly becomes Huck's close friend and guardian. After heavy flooding on the river, the two find a raft (which they keep) as well as an entire house floating on the river (Chapter 9: "The House of Death Floats By"). Entering the house to seek loot, Jim finds the naked body of a dead man lying on the floor, shot in the back. He prevents Huck from viewing the corpse.