Demon Copperhead (Damon Fields) is born in rural Lee County, Virginia, to a single mom who lives in a trailer and struggles with addiction. His dad died before he was born at the mysterious Devil’s Bathtub. His neighbors are the Peggots, whom he considers his grandparents; the grandchild Maggot is Demon’s best friend. Young Demon takes responsibility in his home, helping his mother get to work and finding her lost items. Demon’s mom starts dating a man named Stoner before Demon takes a trip to Knoxville with the Peggots to visit their daughter June and granddaughter Emmy. When they return, Demon learns of his mother’s wedding to Stoner. Soon, Stoner becomes abusive and forbids Demon from associating with the Peggots. 

Stoner locks Demon in his room and then brings the boy to see that his mom has overdosed. At the hospital, a social worker questions Demon, and the next day, his new caseworker, Miss Barks, brings him to a foster home he calls Creaky Farm. Crickson, the proprietor, takes on foster children to supplement his expenses and to work his tobacco farm. Also living in this filthy house are Tommy, Swap-Out, and Fast Forward. Fast Forward is quarterback of the Lee Generals and receives special treatment. The living conditions are disgusting and the tobacco harvest is taxing. Demon impresses the boys with his superhero drawings, including those of characters based on his new roommates. 

After Demon’s mom finishes rehab, they have supervised visits in public, and later, at their home. On one full-day visit at the house, she tells Demon she is pregnant. On Demon’s eleventh birthday, Miss Barks comes to his school to inform him that his mom has died of an oxycontin overdose. He feels angry and abandoned, and the funeral proves that his mother made little impact on her community. Demon thinks people treat him differently as an orphan; even though she comforts him at the funeral, Mrs. Peggot avoids Demon later. When Maggot learns that Demon has nowhere to go for Christmas, the Peggots take him to Knoxville, but he feels unwelcome. Nevertheless, June gives him a nice set of markers and a book with comic strip formatting for his drawings.

Demon is placed with the McCobbs, a poor family with four kids of their own. He is constantly hungry there and expected to contribute, even though he isn’t old enough to work. Mr. McCobb gets him a job where he has to sift through garbage that people drop off behind Golly’s Market. He works there with Swap-Out, and they get to eat the extra hot dogs that go unsold. Miss Barks resigns to pursue her dream of becoming a teacher, leaving Demon abandoned again. The McCobbs move in with family in Ohio. Demon wants to be adopted by the Peggots, but they can’t take on another child. Demon has some money saved, and he begins hitchhiking to reach his paternal grandmother, Betsy, in Murder Valley, Tennessee. The experience is treacherous and miserable; he loses his money to a prostitute at a truck stop, sleeps behind a dumpster, and eventually walks a long distance to his grandmother’s house after his last ride drops him off. She is stunned to see Demon, who looks much like his father and namesake.. 

At Betsy’s house, Demon learns that she raises young girls but not boys. He also meets her brother Dick, who is in a wheelchair and loves to read. Dick becomes the rare adult who feels hopeful for Demon’s future. Betsy comes up with a solution: Demon will live with the husband of one of her girls (who has since passed away) in Jonesville. It turns out the husband is Coach Winfield of the Generals football team. Coach’s smarmy assistant, U-Haul, brings Demon to his latest home, an elaborate mansion, and he meets his foster sister Angus, whom he mistakes for a boy. The two become good friends, and Coach eyes Demon as a potential tight end on the team. At school, Demon admires Mr. Armstrong, from whom he learns about the injustices perpetrated upon coal miners and the whole community by corporations, as well as other systemic inequalities. When Armstrong realizes that Demon is a talented artist, he arranges studio time with his wife, Ms. Annie, who teaches art at the high school. 

Demon remembers his middle school years as some of his happiest. He is motivated by Coach, and he completes a project on his Melungeon roots with the Dick’s help. In high school, Demon plays tight end and works at a farm supply store to save money for a car. While working there, he reunites with Fast and starts to hang out with him on the weekends. He also meets Dori, and the two begin an ill-fated romance that sends them both further down the rabbit hole of addiction. Mr. Peg passes away, his funeral a stark contrast to Demon’s mother’s service. Demon suffers a serious leg injury during a game and is prescribed opioids. He is shaken when he sees the oxycontin prescription but becomes dependent on the drugs nonetheless. After Dori’s father dies, he can’t bear to leave her alone, so he moves out of Coach’s house. They struggle to keep jobs and stave off drug withdrawals while they peddle the last of Dori’s dad’s remaining pills outside a local pain clinic. 

Demon reunites with Tommy and begins a comic strip for the Lee Courier, where Tommy works. The superhero who features in his comic, whom he names Red Neck, is a coal miner based on the workers Mr. Armstrong described. Soon, the strip gains attention and a following in the community. Demon and Tommy sign a one-year contract to produce the comic weekly. Dori cannot deal with being alone; she is always high and accuses Demon of not loving her enough. He considers breaking up with her, but she announces she is pregnant. Not long after, she has a miscarriage and overdoses. He saves her, but the next time she overdoses, Demon finds her dead in their home. 

Emmy has gotten involved in Fast’s drug dealing operation, as a lure for potential customers. June, Maggot, and Demon struggle to locate her, but they eventually go to Atlanta and pull her out of a drug house. She goes to rehab in Asheville, which turns her life around. Back in Lee County, Fast’s lackey, Rose, baits Maggot, Demon, and Hammer Kelly to visit Fast at Devil’s Bathtub. Hammer is on meth and reeling from Fast’s treatment of his former girlfriend, Emmy; he wants revenge. When they get to the waterfall, Fast is naked atop a cliff, while Hammer screams at him and starts to raise his rifle. Fast’s friend Big Bear yells a warning, but his voice causes Fast to stumble and fall to his death. Hammer jumps in after him but is also killed. After this incident, Demon hits rock bottom, chasing highs to escape his feelings. 

June talks Demon into attending rehab, which will then lead to a halfway house in Knoxville. Though he hesitates, Demon eventually gets clean there and bonds with his housemates while learning about city life versus country life. He visits the library, corresponds with Tommy via email, and creates a website where he posts his new comics. Tommy suggests they combine the research and thinking he has been doing about the history of Appalachia with Demon’s art. After he uploads some of the strips to his website, Demon gets a book offer. He returns to Lee County to discuss his manuscript with Ms. Annie, but he instead catches up with several people from his past, including June and Coach. Finally, Demon goes to Coach’s house, where Angus is making arrangements to put the mansion up for sale. Angus wants to take Demon to the ocean, and he discovers that she loves him. They drive toward the ocean together, and Demon feels truly happy.