The film opens with two college students in a bar, talking about a thesis statement for an upcoming paper. One of them makes an argument that America is unique in that it has no real mythological character for granting wishes, such as a genie or leprechaun. The two men are soon joined in conversation by an old man at the bar claiming that America does, named O.W. Grant; the son of a leprechaun and a Cheyenne Indian.
O.W. Grant, who is yet found near Interstate 60, wears a red bow tie, carries a pipe with mysterious powers in the shape of a monkey-head and grants people their wish, often with the macabre twist that the wish manifests exactly as it was worded.
In the opening credits, Grant (Gary Oldman), rides down a city street where a man (Michael J. Fox) opens his car door, causing Grant to fall from his bike and break his pipe. Then a truck runs over and smashes Grant's bicycle along with man's cellphone thus breaking his business conversation. Last thing makes the man infuriated and he says that he would like never to meet Grant. Grant, seemingly amused, asks the man if he wished the event never happened. When the man says yes, green smoke billows from Grant's pipe and the scene begins again. This time, Grant safely avoids the car door. As he watches, the man gets out of his car and is crushed by the oncoming truck. Grant retorts, "Some people just don't know what to wish for."
The story then switches over to Neal Oliver who works at a warehouse in St. Louis, Missouri, at night on the stocking crew that gets food ready to be delivered to local grocery stores. Although he has a rich family, and his dad works as a lawyer, Neal works the warehouse job to not have to rely on his family for spending money. While he aspires to become an artist, he does not have enough faith in his work, and his girlfriend is a psychology major who keeps analyzing him without offering any real support. He also has recurring dreams about a blonde-haired girl (Smart), whom he keeps drawing and painting.
On his twenty-second birthday, his family is gathered in a restaurant to celebrate. Among the gifts and smiles, O.W. Grant, dressed as a waiter, serves them their cake. Neal blows out the candles and tells everyone that he wished for an answer to his life, to which his father presumptuously hands him an acceptance letter to a prestigious law school. Watching from a corner, Grant is intrigued by Neal's wish, considering it one of the few he heard that is not entirely self-serving. As the family goes outside to look at the car (a new red BMW convertible) that Neal's dad bought him (which suits his dad's taste more than it does Neal's), a bucket falls onto Neal's head, knocking him out. Later, he wakes up in the hospital, where a doctor named Ray (Christopher Lloyd) comes in and does a quick sight test with Neal using playing cards. He holds them up quickly and Neal has to name the suit on the cards.
At the end of the test, Neal confidently asks if he got it right, at which Ray replies that he did not, since the cards actually had red spades and black hearts. Ray then gives Neal a small lecture about how things aren't always what they seem. He leaves, and another doctor comes in confirming that they don't have a doctor named Ray on their staff.
Shortly after getting out of the hospital, more strange happenings occur around Neal. At a Chinese restaurant, his fortune cookie 'fortune' reads: 'Oct 15th. Are you sure?' The date is the same day of the law school interview that his Dad had set up. However, when one of Neal's friends looks at the fortune, the letters have disappeared.
While working at his warehouse job, he notices a billboard with the same girl on it that he has been painting in his art pieces. Neal is curious to find out who she is, and calls the billboard company that placed the advertisement, only to have them say that the display is blank. Bewildered, Neal drives back to the location to find that the billboard has now changed to a new image with the girl and a telephone number. Neal gives it a call, and a recorded message tells him that he has an appointment for the next day at a specific time. The next day, Neal goes to his appointment on the 13th floor of the specific building, only to find that the building doesn't have one. Taking a cue from an ad in the elevator (which also has the girl on it), he presses the '10' and '3' buttons on the elevator, and ends up on floor 13.
Once there, he again meets Ray who gives him a package to deliver, but does not tell him what is inside; addressed to a Robin Fields in a town called Danver in Colorado (not "Denver"). Ray then explains the rules of the delivery: if Neal leaves the 13th floor with the package, he must deliver it. As well, he is not allowed to open the parcel or find out what is inside it. Neal is then given a contract, which he signs with a pen, and seals with a drop of blood per Ray's request. Once he has done so, Ray cautions him that there's a killer on the loose, and to be careful. However, when Neal presses for more information, Ray will not continue further. As Neal leaves with his assignment, Ray tells him that he'll find Danver by taking Interstate 60.
Neal checks a number of roadmaps, but there does not appear to be an Interstate 60. Taking a guess, he sets out West, only to encounter O.W. Grant along the roadside. Grant happily greets Neal, and hands him a bag containing a 'birthday present.' The present turns out to be a Magic 8-Ball, which can answer any yes-or-no question that Neal asks it. Shortly after their meeting, Grant gives Neal some directions, and they are soon on the unlisted Interstate 60.
Traveling along the mysterious highway, Neal and Grant discuss such things as the humor found in causing people to recognize the gullible side of themselves, Grant's unfortunate accident that cost him his penis, and the certainty of knowing what to wish for. Grant departs soon after, leaving Neal to run into such characters as:A promiscuous woman (played by Amy Jo Johnson) looking for perfect sex. She leaves the car after Neal tells her that her "perfect sex" will be what she never got from him, because its potential will outweigh any real-life encounter.
The same man who told the two men in the beginning about O.W. Grant. Neal and O.W. encounter him as he walks into a diner and makes a bet that he can eat a gigantic amount of food in an hour without throwing up or relieving himself. He wins the bet, but reveals that he got this ability as a wish, and that it has drained any enjoyment of food he used to have.
A dying and persistently honest ex-advertiser named Bob Cody (Chris Cooper) with lung cancer...and dynamite. He hires Neal to drive him, and approves when he follows his requests (silence and honesty). He later helps Neal in the town of Morlaw.
A lonely mother looking for her slacker son, who turns out to be living in a city where the population is addicted to a government-controlled drug, Euphoria; Kurt Russell is the local police chief with a penchant for dry humor.
A Museum of Art Fraud run by Mrs. James (Ann-Margret) that actually contains real masterpieces posing as fakes that are undetected by the visiting poseurs.
The town of Morlaw, where every citizen is a lawyer who spend their days suing each other, and imprisoning and exploiting unwary travelers on trumped-up charges.
It's here that Neal is finally united with the imprisoned Lynn (Amy Smart), whom he has been painting and drawing. When he gets her released from prison, she turns out to be far from the perfection he expected, swearing in an uncouth and rude manner – but it turns out to be a ruse to make sure that Neal does not just want to get into her pants.
Once they are free, Lynn explains that she had previously met O.W. Grant, and had wished to find the right guy; Neal's experiences were actually tests to qualify her prince—though she hadn't counted on her wish leaving her in jail for one year. After exchanging conversation, they realize that they have much in common and spend the night together at the "Fork in the Road" motel. Neal also makes a painting of the motel in the waking hours of the morning. Neal then leaves to ensure that he delivers the package in Danver, due to the contract he signed. However, Lynn stays behind, as a letter from O.W. Grant cautions her not to go.
However, when driving on the way to Danver, Neal's car matches that of a reported murderer on the loose. He abandons the vehicle, and the police get into a confrontation with the real killer in an identical car, which ends in a fiery car wreck. Neal asks one of the policemen who he was, and replies that he was a St. Louis law school student who went insane and murdered his own father.
After hitchhiking a ride to Danver, Neal finally makes it to the Rainbow Club. Entering a seemingly-abandoned bar, he is reunited with the mysterious Ray, and is stunned when "Robin Fields" turns out to the whimsical O.W. Grant himself, whose insistence at holding people to their tasks prevented him from reclaiming his package earlier in the film. Upon taking delivery of the package (which holds a replacement monkey-head pipe for O.W.'s broken one), Grant uses his magic powers to "warp" Neal back in time, where he wakes up in the hospital before he first encountered Ray.
Leaving the hospital, Neal finally confronts his father and asserts his right to live his life without his father's interference, and then proceeds with his sister to an art gallery at her insistence, confused as to why he'd need to be there with none of his work submitted. Once there, he realizes that his painting of the "Fork in the Road" was submitted to the art gallery. A few moments later, Grant appears, reminding Neal of the value of honesty and humor. A girl who resembles Lynn (also Amy Smart) talks to him, interested in commissioning him to do a series of paintings on roadside motels and diners. As they chat, Grant is seen talking softly to Neal's sister. "You have a birthday coming up, right?" he says, smiling mischievously. "Don't forget to make a wish..."James Marsden as Neal Oliver
Gary Oldman as O.W. Grant
Amy Smart as Lynn Linden
Christopher Lloyd as Ray
Chris Cooper as Bob Cody
Kurt Russell as Captain Ives
Michael J. Fox as Mr. Baker
Ann-Margret as Mrs. James
Amy Jo Johnson as Laura
John Bourgeois as Daniel Oliver, Neal's father
Roz Michaels as Marlene Oliver, Neal's mother
Wayne Robson as Deep Stomach
Amy Stewart as Nancy Oliver, Neal's sister
Rebecca Jenkins as Susan Ross
Tyler Kyte as Philip Ross
Deborah Odell as Valerie McCabe
Review aggregation website Rotten Tomatoes does not yet have a Tomatometer for Interstate 60.
The DVD includes several deleted scenes and the "bridges" where they would be placed in the film. They include:Neal visits a government office where he seeks information about Interstate 60 that the client service officer repeatedly tells him does not exist. The officer explains the American Interstate Highway System to Neal. Neal discovers that if I-60 did exist, it would be oriented west to east and be north of Interstate 40 and south of Interstate 70.
When told by the man in the bar about O. W. Grant at the film's beginning, a waitress tells Neal that she had never seen the man before but he had won a large amount of bets by consuming large quantities of alcohol in a brief time without throwing up or urinating. This is the same man who appears later in a diner and makes similar bets that he can eat large amounts of food without releasing them through similar processes. The man admitted he acquired this quality through a wish from O.W. Grant but did not enjoy it, because in addition to being able to eat without stopping, he now must do so to avoid starving.
After a co-worker tells Neal that work is the same as high school due to all the rules and punishments, Neal chats with another co-worker named Otis. Otis enjoys his job due to working night time hours makes him feel special. Neal asks Otis if he thinks work is like high school and Otis laughs and said that he never went to high school.
Neal meets his father in his office saying that he doesn't want to be in a pigeon hole. His father says that everyone in the world is in a pigeon hole, even starving artists; there are good pigeon holes and bad pigeon holes so it is better be in a good one.
At the beginning of his road journey, Neal receives a call on his mobile phone but shuts it off narrating that the only freedom left in the 21st Century is to be incommunicado.
At the police station in the city where drug addicts are given a highly addictive but totally legal drug that they pay for by being in the town's work force, Neal has brought a mother searching for her son. The son has only an interest in the drug and no interest in his mother. Given a choice of staying behind and seeing her son and maybe having him work for her, leaving and never seeing her son again, or taking the drug and becoming a fellow addict, the mother asks Neal what he thinks she should do. Neal relates a story of visiting his grandmother in a nursing home. When she slipped into dementia, Neal said he still remembered the times they had together, and even though she did not, it still made him happy; therefore, she should stay. The mother cries that she'll never be a grandmother and takes the drug.
After leaving the hospital at the end of the film, Neal breaks up with his girlfriend who calls him a loser and that artists starving for their work only exist in the previous century.