Investment banker Harold Lee, portrayed by John Cho, navigates the pressures of his first job while dealing with his colleagues who insist he handle their work over the weekend. Meanwhile, his roommate Kumar Patel, played by Kal Penn, finds himself in a rather unconventional situation during a medical school interview with Dr. Willoughby, portrayed by Fred Willard. Although highly qualified, Kumar intentionally sabotages his chances of acceptance after a phone call from Harold distracts him during the interview. Driven by a desire to smoke some marijuana, the pair embarks on a memorable adventure after seeing an advertisement for White Castle's hamburgers.
Harold harbors feelings for his attractive neighbor, Maria, played by Paula Garces, but struggles to express them. After indulging in some weed, they set out together to satisfy their fast-food cravings. Neighboring stoners Goldstein (David Krumholtz) and Rosenberg (Eddie Kaye Thomas) decline to join them, too engaged in watching a Katie Holmes film. Their journey begins with trouble as Kumar throws coins into a toll booth, yet the machine doesn’t register, causing frustration among other drivers.
Arriving at a White Castle location only to find it's been replaced by a "Burger Shack," Harold and Kumar are informed by a drive-thru worker, played by Anthony Anderson, that another location exists in Cherry Hill. Stopping at Princeton University to acquire more marijuana, Kumar encounters student Bradley Thomas (Dov Tiefenbach) and ends up losing their cannabis stash while escaping campus security. This unfortunate incident causes them to miss a party that Cindy Kim, a studious Princeton student with a crush on Harold, had invited them to.
Their adventure takes another turn when a raccoon breaks into their car and bites Harold, leading them to a hospital where Kumar’s father and brother work. Nonetheless, Kumar manages to don ID badges and secures medical marijuana. Unexpectedly, he is mistaken for his brother by the OR nurse, portrayed by Ryan Reynolds, which leads him to perform emergency surgery on a gunshot victim, astonishing everyone when he saves the patient's life just in time. This fortuitous encounter eventually leads them closer to their fast-food quest.
In their pursuit, Kumar spots Maria at a movie theater and attempts to connect Harold with her, only for Harold to panic and crash their vehicle. They're helped by a tow-truck driver named Freakshow, played by Christopher Meloni, whose insistence on a peculiar proposition sends Harold and Kumar fleeing in disgust. They then meet a hitchhiker, portrayed by Neil Patrick Harris, who is in an altered state and inadvertently drives away with their car.
Their misadventures continue when they confront a racist officer, leading to Harold's arrest after a physical confrontation. Inside the jail, he encounters Tarik Jackson (Gary Anthony Williams), an insightful African American man detained simply for being himself. Kumar, ever resourceful, distracts the police with a 911 call to execute a daring rescue for Harold.
Along the way, they befriend a cheetah that turns out to be quite the companion after sharing some marijuana, and together they journey towards White Castle. A series of unfortunate events shatter Harold's laptop, which housed his work, but after an altercation with some extreme sports punks, they concoct a plan that involves stealing a truck to make it to their destination. Their road trip leads them to an edge of a cliff where they make a daring hang glider flight down to White Castle.
Upon placing their orders to be greeted by disappointment due to a lack of funds, Neil Patrick Harris returns from earlier, offering to pay for their meal to make amends for their previous car theft. This pivotal moment sparks revelations for both Harold and Kumar—Kumar contemplates his true aspirations in medicine while Harold confronts his irresponsible co-workers about their cowardly actions.
In the end, after an emotionally charged moment with Maria, where Harold finally admits his feelings, they leave on a high note with plans to follow her to Amsterdam. As the credits roll, justice is served against the racist officers, setting up a fitting conclusion to their outlandish journey.
