The novel begins somewhere near Barstow, one hundred miles southwest of Las Vegas. The narrator, Raoul Duke, is driving a bright red convertible. Both he and his passenger (who is also his attorney) have taken a large amount of drugs and are just starting to feel the effects. Duke explains that he is a journalist who has been contracted by a magazine to cover the Mint 400 motorcycle race in Las Vegas. He has brought his attorney (and friend) along for the weekend. The men have amassed a huge stockpile of drugs in the trunk of their rental car, including ether, amyls, cocaine, pills, LSD, and marijuana.
On the way to Vegas, the two men pick up a young hitchhiker. However, they quickly frighten him with their erratic behavior and he leaps out of the convertible. Duke and his attorney then proceed to Las Vegas alone. In a brief flashback, Duke explains that the magazine sent him $300 for trip expenses, but he and his attorney have already spent much more than that on drugs, the convertible, and a high-quality tape recorder.
The men arrive at the Mint Hotel in Las Vegas just as the LSD they have ingested is finally kicking in. Hallucinating heavily, Duke struggles to compose himself and is only able to check in with his attorney’s help. The men receive a message from Lacerda, the photographer with whom Duke will be working. Lacerda wants to meet with Duke so that they can discuss the assignment. Duke gets his press badge, after which he and his attorney finally check into their hotel room. They order room service, eat mescaline, and watch the news. On a whim, Duke decides to enter his convertible in the Mint 400, but the attendant is hostile so he decides against it.
Although they have been up all night, Duke and his attorney manage to arrive on time for the beginning of the race the next morning. While waiting for the event to start, they drink beer with a Life correspondent. The race is exciting when it first begins, and the men enjoy watching the first few groups of motorcyclists leave the starting line. However, the Mint 400 is an off-road race through the desert and the rising dust soon makes it impossible to see what is happening. Duke approaches some spectators in a dune buggy covered with patriotic imagery and tricks them into harassing another journalist. Pleased with his prank, Duke returns to the bar for a day of heavy partying.
Later, Duke drives the convertible down the Strip and argues with his attorney about whether to see Guy Lombardo or Debbie Reynolds perform. Duke suddenly finds himself parked on the sidewalk outside the Desert Inn, which settles the debate because that is where Reynolds is performing. Duke's attorney bribes a parking attendant to move the convertible. They try to get into the show without tickets by claiming that they are friends with Reynolds. They eventually succeed but security guards soon removes them for their ridiculous behavior.
The men visit Circus-Circus, where they are planning to ingest ether, but the mescaline that is already in their systems begins to make them paranoid. They return to their room at the Mint and convince themselves that Lacerda is conspiring against them. Duke's attorney begins to plot revenge against the photographer, so Duke urges him to take a shower while he parks the convertible. When Duke returns to the room only a few minutes later, he finds that his attorney has eaten an entire blotter of acid. As Duke's attorney becomes agitated and uncontrollably violent, Duke has to blockade him in the bathroom so that he can get some sleep.
Duke recounts his first few LSD experiences. He once tried to get tips from Dr. –––, a local acid guru in San Francisco, but got the sense that Dr. ––– disapproved of his violent lifestyle. On another occasion, he accepted acid from a street person, but spilled some on his shirtsleeve. Another stranger sucked it off his shirt without permission. Duke then explains that the counterculture of the 1960s was uniquely idealistic and mourns its decline.
The men receive a massive bill from the hotel and realize they have run out of money. Duke's attorney decides to return to Los Angeles. Duke, who is completely broke, manages to sneak out of the Mint Hotel without paying. Just as he is leaving, he receives a telegram from his attorney saying that Rolling Stone is offering him a large assignment that comes with a massive payment. He is to cover the National Conference of District Attorneys’ seminar on illegal drugs.
Duke checks into the Flamingo before the telegram boy can figure out that he is leaving the Mint without settling his bill. He waits for his attorney's return, taking some time to think over the assignment. He soon begins to have a drug-induced, paranoid ‘freakout’ and flees Las Vegas in his convertible. In Death Valley, a cop pulls Duke over for speeding but lets him off if he promises to take a nap at the next rest stop. There, Duke phones his attorney, who convinces him to return to Vegas and complete the Rolling Stone assignment.
On his way back to Las Vegas, Duke has a brief aggressive spell and fires his attorney's gun in the desert. He realizes that his actions could get him in trouble and decides to purchase some ether and liquor at a convenience store instead. Rolling Stone has reserved a Cadillac for Duke, so he abandons the convertible at the airport. When he checks into the Flamingo Hotel, he realizes that all of the police officers attending the conference are also staying there. To his surprise, his attorney has already arrived. When Duke gets to their room, he finds his attorney naked and about to have sex with a young woman named Lucy, whom he met on the airplane. Lucy is paranoid and behaving strangely. Duke's attorney explains that she had never tried drugs before, so he decided to give her a tab of LSD. The men realize that Lucy will likely be angry with them when she comes down from the acid trip and abandon her at another hotel.
Once Lucy is gone, the men take adrenochrome, a drug notorious for its intense high. The next morning, they attend the conference, keynoted by Dr. E.R. Bloomquist. Duke spends most of the conference privately noting inaccuracies in information the supposed "experts" are parlaying. Eventually, Duke and his attorney become frustrated and leave, stopping briefly at the bar, where they lie to a Georgia police officer about ‘dope fiends’ committing violent crimes in Los Angeles.
While Duke and his attorney are driving along the Strip, the attorney heckles some tourists, angering them. Duke stops at Texaco and pumps the tires dangerously full of air in hopes that the Cadillac will coast more easily around corners. Surprisingly, the tires do not explode and the men make their way to North Las Vegas, where Duke's attorney behaves aggressively toward a waitress in a diner. For one whole chapter, Thompson relates the events of his narrative as a transcript of raw sound recording because Duke and his attorney were too high to remember what happened. The transcript chronicles the men's day trip to Boulder City, a desolate town outside of Las Vegas. They ask the waitress at the taco restaurant where to find the American Dream, and she recommends they visit a bar called the Old Psychiatrist’s Club, which is frequented by junkies. They go there only to find that it burned down a few years before.
Duke drops his attorney off at the airport by driving onto the runway and pulling up directly next to the airplane. In his final hours in Las Vegas, Duke drives down the Strip and ponders the relationship between money, power, and appearances in this city. He recalls a friend’s story about being arrested by Las Vegas cops simply for his appearance and sitting in jail for days while two drug dealers were released with the help of an expensive lawyer. This rumination broadens into a discussion of the disintegration of the ‘60s counterculture. Back at the Flamingo, Duke realizes that he and his attorney have left their room in a horrific state. However, he is comforted by the fact that they convinced the maid that they were police officers and recruited her as a confidential informant. Duke hopes that she will clean their room without reporting its condition.
He meets his friend Bruce Innes at the Circus-Circus in hopes of buying an ape, but the ape’s owner has left by the time Duke arrives. His visit to Circus-Circus ends abruptly, though, because a security guard recognizes him as the companion of "Dr. Gonzo" (the fake name Duke's attorney uses) and escorts him out.
Back at the Flamingo, Duke finds that his car has been wrecked, and suddenly recalls driving it into Lake Mead. He takes a cab to the airport and flies home, paranoid the whole time about the number of cops wandering around the airport. Fortunately, the flight attendant is kind to him, and Duke arrives in Denver without incident. He briefly considers buying a Doberman but instead settles for purchasing some amyls at the pharmacy. As the text ends, Duke heckles two Marines leaving the airport restroom.