Raoul is a journalist assigned to cover the Mint 400 off-road vehicle race for a New York sporting magazine. Operating under his personal ethos of "Gonzo journalism," he treats his assignment as a subjective, immersive quest to find the elusive "American Dream." He travels with a massive collection of illicit substances, which severely distorts his perception of reality and subjects him to extreme paranoia. Despite his heavy intoxication, he serves as the slightly more reflective and cautious half of his traveling duo, frequently worrying about hotel bills, police attention, and the threat of imprisonment.

Dr. Gonzo is Raoul's attorney and traveling companion. He operates entirely on unrestrained instinct, enthusiastically embracing their extreme drug binge and frequently pushing their situations into dangerous, volatile territory. Whether he is threatening service workers with a knife or demanding a radio be thrown into his bathtub at the peak of an acid trip, he represents the violently aggressive and reckless side of their chaotic journey.

Lucy is a young woman who meets Dr. Gonzo on a flight to Las Vegas while running away from home. Having never even consumed alcohol before, she is given LSD by Gonzo and quickly becomes heavily intoxicated and disoriented. The duo views her as a "controlled experiment," demonstrating how easily an innocent, sober person can be corrupted and mentally destabilized by exposure to hard drugs.

The Hitchhiker is a young man looking for a quiet ride through the desert. He quickly realizes his mistake after entering Raoul and Gonzo's rented convertible, as the heavily intoxicated duo subjects him to terrifying, incoherent ramblings about the American Dream and attacking animals. His intense fear prompts him to flee the vehicle at the first opportunity.

Lacerda is the photographer assigned to work with Raoul on covering the Mint 400 off-road race. Due to the duo's heavy drug use and paranoia, he becomes an unintended target of Gonzo's suspicion, with Gonzo falsely claiming the photographer tried to steal a woman from him.

Dr. Bloomquist is a keynote speaker at the District Attorney's conference on narcotics. He presents severely outdated and bizarre theories about drug culture to an audience of police officers, illustrating the massive disconnect between established law enforcement's understanding of narcotics and the actual reality of the drug scene.

The Highway Patrol Officer enforces the law on the desolate roads outside Las Vegas. Despite catching Raoul driving erratically and speeding, he exercises surprising leniency, offering to let Raoul off with a warning provided he pulls into a nearby rest stop to get some sleep.

The hotel clerk at the Flamingo manages check-ins during the heavily attended police narcotics conference. Frustrated by the constant demands of law enforcement, he uses his minor authority to antagonize a late-arriving policeman, inadvertently creating a distraction that allows Raoul to slip by and secure his room reservation without scrutiny.

A waitress working in a diner in a marginalized area of Las Vegas. She attempts to serve Raoul and Gonzo but ends up being crudely propositioned via a note on a napkin. When she takes offense and mentions calling the police, Gonzo pulls a knife on her and cuts the telephone cords.

A housekeeping employee at the Flamingo hotel who accidentally walks in on a horrifying scene of filth. She discovers a violently ill Dr. Gonzo vomiting in a closet, but is quickly manipulated into silence when the duo flashes a fake police badge and offers her a fictitious job as a police informant.

Bruce Innes is a friend of Raoul's located at the Circus-Circus casino. He contacts Raoul to arrange the sale of an ape, matching the bizarre and chaotic nature of Raoul's trip, though the deal falls through when the animal is reportedly arrested for attacking an elderly man.