This novel is told in first person point of view from the perspective of the teenaged Huckleberry Finn. He begins the book by recapping what happened in the prequel, The Adventures of Tom Sawyer; then he tells the reader that he is currently living with the Widow Douglas because his father, whom he calls Pap, tends to be irresponsible. He and his best friend Tom like to sneak out at night and even form what they consider to be a "gang," which consists mostly of them pretending to do bad things to people.

Huck's Pap returns to town and forces Huck to live with him in a cabin the woods. Huck doesn't mind not going to school or keeping clean, but he doesn't like the beatings that he periodically receives from his father, so he decides to run away. In order to keep his father from looking for him, he decides to make it look like he has been killed using blood from a pig he found and by ransacking the cabin. Huck sneaks away and settles on Jackson's Island where he coincidentally runs into Jim who Huck knew as Miss Watson's slave. Jim explains that he is running away because he overheard Miss Watson talking about selling him, and he has decided he wants to make it to a free state in order to have the opportunity to buy his wife and children out of slavery. Huck agrees to help him in this quest, which pleases Jim greatly.

Jim and Huck head down the Mississippi River together. They stop sometimes to check out various steamboats or pick up some supplies. At one point they find a dead man on a broken house boat. Another night they become separated in a fog. Later their raft is hit by a huge steamboat, and Huck is forced onto shore.

He stays with the Grangerford family and becomes particularly close with Buck, who is about Huck's age. The Grangerfords have a family feud going with the Shepherdson family, which causes them to shoot at one another. One day Buck is killed during a shoot out, so Huck escapes back to Jim who has been working to repair the raft. They head down the river once more.

When they have just about reached the turning point that would take them onto the Ohio River, which flows north to the free states, two con men force their way onto the raft. They convince Jim that they are a King and a Duke who deserve to be treated accordingly. Huck knows they are lying but doesn't want to cause trouble. They do various schemes to try to raise money, including acting out some Shakespearean scenes. The audience members don't appreciate Shakespeare, so they laugh at the two men. The men decide to get back at the town by changing the show to one of the men dancing naked on the stage. The paying audience becomes angered by this alteration in the performance, so they return the following night with fruit and other items that they are prepared to throw at the performers; however, the King and the Duke are smart enough to take their money and leave.

They all lay low for awhile until the King and the Duke find a new way to make money, which involves pretending to be the brothers of a deceased man. Huck acts as their servant as they convince the three daughters of Peter Wilks that they are the girls' uncles. They get a hold of the $6000 that Peter left to his brothers and hide it in the King's bedroom, but Huck steals it and stuffs it in the coffin of the dead man, intending to return it to the girls. When another set of brothers show up claiming they are the real relatives, it leads to the townspeople digging up Peter's coffin with the money still inside. Huck, the King, and the Duke escape the town with nothing to show for it.

Next, the King and Duke decide to make a fake poster advertising a reward for Jim to use as bait for a family to buy him thinking they will get the full reward amount. Huck is terribly upset to learn that Jim has been captured, so he opts to free him once again. Huck finds Jim on Phelps farm where he ironically has to pretend to be his own best friend Tom Sawyer because the farm belongs to Tom's aunt and uncle, who have been expecting Tom to arrive. When Tom does arrive, he pretends to be Sid Sawyer and agrees to help Huck free Jim again. Tom's plan for freeing Jim, however, involves a heap of difficulties for Jim, but Jim puts up with all of it because he is so pleased to have two white boys helping to release him. Finally, the boys escape with Jim, but Tom is shot in the foot during their getaway, so Huck must find a doctor. The doctor returns to Phelps farm with a repaired Tom, and Jim is put back in the cabin where he was kept prisoner. When Tom finds out where Jim is, he becomes terribly upset and reveals that Jim is actually a free man. Miss Watson had died two months earlier and freed him in her will. Then Tom's Aunt Polly shows up and explains who everyone is, so they can all go home. Jim also tells Huck that the dead man they found on the houseboat awhile back was Huck's Pap, so he won't be bothering Huck any more.