Jesse (Ashton Kutcher) and Chester (Seann William Scott) are two dim-witted potheads who wake up one morning and can't remember what happened the night before. There is a lifetime supply of pudding in the kitchen. Their girlfriends The Twins, Wanda (Jennifer Garner) and Wilma (Marla Sokoloff), call and remind them its their one-year anniversary. Jesse and Chester decide they must have gotten the twins gifts and they are in the car. They go outside and cannot find Jesse's car. It is decided that they need to practice altered conscious memory retrieval by putting themselves into the state of mind of the night before. They go to their friend Nelson's (David Herman) house where they have a talk about reclaiming their memory as well as watch Nelson's cannibas-loving dog smoke on a pipe. Later, they are hungry from smoking all that weed and decide to go to Chinese Foooood, a drive-through Chinese restaurant where the beligerent woman, who takes their order, annoys Jesse so much by repeating "and then?" that he destroys the drive-up speaker.
Being a pacifist against violence, Nelson drops them off on the street where they meet the local hot girl Christy Boner (Kristy Swanson), "el fuego of all that is el fuego". They are surprised when she recognizes them and tells them what a nice time she had the night before. Then her jock boyfriend Tommy (Charlie O'Connell) shows up with his friends and threatens "stoner bashin' time" if Jesse and Chester talk to Christy again.
In an effort to retrace their steps, they end up at the Kitty Kat Club, a local strip bar where they are well known by the dancers, further perplexing them as to what exactly happened the night before. Here Jesse meets Tania, a "gender challenged male" who angrily tells him that she gave him a suitcase full of stolen money to keep safe for her and she wants it back.
Jesse and Chester decide to go to The Twins house to try to remember the night before. They try to help The Twins clean the house but fail when they accidenly spill garbage all over the living room floor. Wilma and Wanda kick them out proclaiming they never to anything right.
At this point the Jesse and Chester are kidnapped by a group of space nerds who follow Zoltan (Hal Sparks). The nerds tell them that last night they were in possession of a mysterious and powerful device called the Continuum Transfunctioner, and the nerds are searching for this device.
Upon being dropped off back on Main Street, the guys visit the local tailor, Mr. Lee, who gives them their special suits that they ordered the night before. They both find matching tattoos on their backs in which Jesse's reads 'Dude' and Chester's reads 'Sweet'. Chester finds a Rubiks Cube in his suit. They also realize they have cell phones and have leased a convertible sportscar. Sweet!
Out on the street, they are approached on the street by a five strange-looking women, wearing black jumpsuits, who proclaim themselves 'Hot Chicks'. They offer to give Jesse and Chester "erotic pleasure" in exchange for the Continuum Transfunctioner. Tania once again shows up asking for her money and the five Hot Chicks disappear. At this point Jesse and Chester are arrested by the police after being mistaken for thieves and are interrogated at the police station by a pair of overzealous beat cops. Once they are proved innocent, they find out that their car was found last night by the police, but unfortunately it was impounded by the sight-challenged officer Rick.
Meanwhile, the five Hot Chicks travel to the pizza parlor where Jesse and Chester work to look for them, when they meet Tommy and his goons engouring on some pizza just as Kristy has had enough of Tommy's macho attitude and she walks out on him. The Hot Chicks approach Tommy and offer him "erotic pleasure" if they can get the Continuum Transfunctioner away from Jesse and Chester. Tommy sends them to the workplace of The Twins, who work as councelors at a local blind school and summer camp. Wilma and Wonda meet the Hot Chicks whom ask the whereabouts of Jesse and Chester, and they become angry. At the same time, Tommy and his friends kidnap Nelson, and calls Jesse and Chester to arrange the transfer of Nelson for the Continuum Transfunctioner.
After leaving the police station, Jesse and Chester meet a pair of gay-looking Nordic dudes who claim to be the Keepers of the Continuum Transfunctioner. They lent it to Jesse and Chester the night before. But the guys are more suspicious then ever and shake the two mysterious guys off. Our heroes go home to their house only to meet The Twins who break up with them. Overcome with love for The Twins, Jesse and Chester realize they must have really good anniversary gifts in the car and resume the search.
Jesse and Chester arrive at a car impound lot where they are told that their car was sold at auction, but are able to get the address of the buyer. At this point they are once again approached by the Nordic dudes and they send them to Chinese Foooood to keep them busy with the non-English speaking Chinese lady over the order intercom.
While they are on their way to the buyer's place, Jesse and Chester are kidnapped by the space nerds again and taken to their leader's country house, only to find out The Twins are bound and gagged and being held hostage by Zoltan until he receives the Continuum Transfunctioner.
Jesse and Chester are allowed to leave and they follow the address of the man who purchased their car at auction to a very secure ostrich compound. They sneak over the fence in only to be attacked by several ostriches and are then captured and caged for poaching by the compound owner Pierre (Brent Spiner), an eccentric ostrich breeder. Jesse and Chester are freed when Chester knows the answer to the question Pierre poses thanks to his constant watching of Animal Planet. Pierre offers to give them their car back only to discover it has been stolen from the compound. All Pierre was able to recover was a locker key from a locker at Captain Stu's Space-O-Rama, a local minature golf course and video arcade.
As nightfall arrives, Jesse and Chester arrive at the Space-O-Rama and find a stash of cool stuff in the locker, including Captain Stu tickets, a cool straw, and the suitcase full of money. Tania and her transsexual boyfriend, Patty, show up and take the money. Jesse and Chester use the Captain Stu tickets to buy a fake Continuum Transfunctioner. They then call Zoltan and Tommy claiming that they have the Continuum Transfunctioner. Zoltan shows up and trades The Twins for the fake Transfunctioner. Just then, Tommy shows up and steals the fake Transfunctioner and lets Nelson free. The five Hot Chicks and the two Nordic Dudes show up, both claming to be the Keepers of the Continuum Transfunctioner. Even Christy Boner shows up and has a quick meeting of the minds with Nelson, while Jesse and Chester's boss, also shows up with pizza after Chester annoymously called requesting pizza.
Just then, Chester then solves the Rubiks Cube (which he has been working on the entire time since finding it in his colored suit) which suddenly glows and morphs into a strange silver-painted globe and it is revealed to be the Continuum Transfunctioner. The Transfunctioner is now activated and will destroy the universe unless the true Keepers can turn it off. Jesse and Chester decide who the real Keepers are by asking a question about the 18th hole of putt-putt the night before. Only the real Keepers know that they won a lifetime supply of pudding by getting a hole in one. The two alien Nordic dudes answer correctly and are given back the Transfunctioner which they deactivate it.
The universe is saved until the Hot Chicks scream with rage and morph into a "Super Hot Giant Alien Chick" and go after the Continuum Transfunctioner. The Nordic Dudes attempt to use the device to bannish the giant to Hoboken, New Jersey, only to get flung aside, and the Transfunctioner lads in Jesse's hands. The Giant Alien Chick then eats Tommy, while Christy reacts with indifference. Jesse and Chester are forced to run outside in the putt-putt golf course and the Giant Chick follows them. Jesse and Chester must activate the Photon Accelerator Annihilation Beam to destroy her. Chester once again saves the day thanks to his love of Animal Planet by using a straw as a tool to push the button. Tommy however is still alive when he gets blown out of the giant alien chick's body.
Christy falls in love with Nelson. The Nordic Dudes take the space nerds to a party in the Crab Nebula. Everyone's memory is erased by the Nordic Dudes as they use the Continuum Transfuctioner to reverse time to the very begining of the movie.
In the morning, Jesse and Chester can't remember the night before, but at least they find the car outside (which was hidden behind a mail truck this whole time) and drive to The Twins house where they exchange gifts and receive a special gift from the Keepers of the Continuum Transfunctioner. They get in the car to drive and get some Chinese Foooood.