Highway 61 is a dramatic coming of age film about an orphan with dreams. Pokey, is an orphan and works as a barber in a small town in Canada. He dreams of one day leaving this town and becoming a famous musician. One day, Pokey discovers a dead body in his backyard. The body is frozen and Pokey has no idea how long it has been there. He is alarmed and has no idea what to do. Along comes Jackie, a tough woman who tells Pokey that the dead body is her brother.
Jackie is lying and it turns out she wants to use the body to smuggle drugs. Pokey is very naïve and he believes Jackie when she tells him she wants to bring her brother's body to the United States to bury him. The two set off on road trip, in Pokey's dead parents car, with the dead body hidden in the trunk.
While on their way down south, Jackie and Pokey are followed by a frightening looking man named Mr. Skin. Mr. Skin believes that the dead body in Pokey's possession owes him his soul. In turns out that Mr. Skin believes that he is Satan. When the dead man was alive, he sold his soul to Mr. Skin. Mr. Skin is not determined to collect on their deal so he pursues Pokey and Jackie down Highway 61. Pokey is blissfully unaware of all this.
Pokey also begins to find himself falling in love with Jackie, who he still has not figured out is a drug dealer. Throughout the road trip, Pokey eventually learns that truth about Jackie, Mr. Skin, and the dead man. As a result, he begins to grow up and open his eyes to the world around him.