This is a dark, twisted, gorey, horror, murder mystery, comic, mushy romantic love story, with rape, murders, devils, and lots of religious references, mostly to demons, hell, hellfire, damnation, and the devil. (There are too many satanic references in the movie to mention, but some of the good ones besides the horns that grow out of the protagonist's head, are a red devil LSD tab that his brother takes, the fact that the most evil person in the movie lost two fingers on his hand that makes it a permanent "devil horn" symbol, and the protagonist's car - a red Gremlin. There are also lots of license plate numbers, diner names and character names that reference the bible, and there are a few references to the movie's titular horns, especially the fact that the protagonist's brother is a musician who plays the horn. And of course, there are lots and lots of snakes. A priest tells the protagonist "When Satan was banished from Heaven, he was cursed to crawl the earth like a snake." So you don't even have to figure out for yourself that the snakes in this movie are satanic symbols.
In the Pacific Northwest town of Gideon Bay (another biblical reference) the protagonist, Ignatius (ditto) Perrish (aka Iggy) (Daniel Radcliffe) is a radio DJ who's on leave because he is suspected to have killed his girlfriend Merrin. Iggy says that when people look at him they see a devil, so now he has to look the part. Then he wakes up with giant devil horns starting to grow out of his forehead.
He sets out to try to find Merrin's real murderer, and discovers that people are not reallly shocked by his horns. Instead, the horns make them tell him the truth, saying things that they would usually keep secret. This is where the comedy comes from in this genre mash-up. The funniest scene is when Iggy jokingly tells the journalists who are constantly following him that if they beat each other up, he will give an exclusive interview to the survivor, and they actually start beating each other up with their equipment.
After Iggy's horns grow to their full size, the snakes start to appear. He discovers that along with the ability of his horns to make people tell the truth, he can use the snakes as weapons to extract revenge. A waitress lied to the police, and her testimony will surely help to convict him. So he waits until she's in her car and sends several snakes inside to bite her. Iggy's brother is tortured by drugs and snakes, because he covered up the truth. We also see a shot of Iggy's dead girlfriend covered with snakes to show the horror of the crimes against her. Then finally the real murderer confesses and starts shooting people until Iggy transforms into a devil, sending snakes to wrap themselves around the killer's body and crawl into his mouth, killing him in a most horrible manner.
The snakes in the snakebite scene and the final scene are mostly CGI, but I think some real snakes are used in the movie also in some scenes.