The story begins in St. Louis, Missouri, where Gary Newton is saying his last goodbyes to his patients at the nursing home before he goes to follow the Lewis and Clark trail. He tells the patients that Kurt will take over and that he is not that bad, even though he is grungy. Kurt walks in and surprises Gary with a band (quite possibly based on Guns N' Roses due to the fact that their style, instruments and lead singer's voice all share similarities to the band) that sends the patients into shock because they are so loud. Meanwhile Mike is in bed with a girl named Julie. When he calls her by the wrong name, "Sandy", she doesn't care. In the morning Julie's mom walks in to find them. She screams to Julie's father, Officer Dick, to hurry there. Gary's father has just given Gary the speech about the importance of his trip, and how he would be dead if anything happened to the SUV. Gary slowly pulls out of the driveway and starts driving just a few blocks from his house. Mike jumps out the window and out into the front yard as Dick gets a baseball bat. Gary is surprised when Mike jumps in the car. He sees Dick in the rear-view mirror, and speeds away. Julie calls her fiancé to tell him the wedding is off. Dick is angry, because it was the police chief's son—that was the only way he was going to be able to move from a trooper to a desk job, with a sizable pension. When Gary tells him about the trip, Mike decides he's going too. Mike asks his parents, but they are drunk and asleep so he takes it as a yes. Gary is dreaming about Lewis and Clark telling him that Mike picked up a hitchhiker while he was sleeping. When Gary wakes up, he sees a smelly hitchhiker next to him. But Mike claims the hitchhiker is harmless. Gary agrees when he hears the man's knowledge of the trail. He says he can lead them to a certain spot, so they say OK, but when they get there, the hitchhiker robs them of their clothes, money and he takes the car. Elsewhere, Officer Dick suits up on his motorcycle to look for Mike. So the guys sleep overnight in the woods. They kill and eat a rabbit for food. In the morning they realize they are just in a big backyard. They also find out the rabbit they ate was a little girl's pet rabbit. The little girl's mom calls the cops and they are arrested. They tell the cops about the hitchhiker. When their story checks out, and are told that their SUV is in an impound lot. They are given new clothes and are released from jail only to be greeted by a mob of angry evangelists with reporters, but they are picked up by actual devil worshipers who heard about their story and sympathize with them. They jump and tumble out of the devil worshipers' truck next to an impound lot where they find the totaled SUV. Gary reflects on the fact that "This trip went exactly as planned...and then [Mike] showed up." To make it up to him, Mike decides to reveal the hidden stash of money worth $250 in his boot to him and prompt Gary to start their own trail he would dub "the Gary and Mike trail" rather than go home and face his dad. They buy a junker of a 1964 Bel Air for $200. They spend their other $50 to buy a new rabbit for the little girl whose rabbit they'd eaten. But as they drive away, the bunny runs under their car and is smushed. So it ends by them driving, headed for nowhere in particular, away from home.

On their way through the Bible-Belt in fictional Wenville, Texas, they stop to get some food. They pull in to a Jesus-themed restaurant, aptly named "Baptist Burger", whereupon Gary and the drive-thru clerk become smitten with each other. In hilarious sit-com fashion, he fails every time to notice that she has a growth that covers half her face, but Mike sure does...until Gary goes to her house to meet her. Meanwhile, Mike tries to win a Hotrod in a "hands on the Hotrod" contest.

The duo now find themselves at a Phish concert in Vermont where Gary accidentally swallows 4 hits of acid. When he comes to his senses, he discovers he's married to a 35-year-old hippie woman (voiced by Shannen Doherty) with three kids. Officer Dick also manages to find the duo's car after tracking them for so long and seeks to exact his revenge on Mike, under the cover as a hippie himself. Meanwhile, Mike discovers the secret evil behind the band's unwarranted success. This episode features a strata-cut animation sequence by David Daniels.

Gary and Mike go on MTV's Road Rage (a play on Road Rules) and visit Mike's brother, Ben in Santa Fe, New Mexico. Ben gets jealous of Mike because he becomes more popular than him, and Gary meets a new "friend". WWF wrestler Chyna makes a guest appearance and falls in love with Gary's new "friend" at the end of the episode. Officer Dick catches up with Ben, whom he believes is Mike under an assumed identity, and shoots out the tires of his SUV which he won at the end of the Road Rage program.

Gary and Mike enter the nation's capital, where they're in desperate need of money...so they hunt down a friend of Mike's mom. Soon, they're working on a campaign for a crusading senator's health care legislation. Gary seems to be helping a great deal, but without knowing it is causing more trouble than the campaign can stand, meanwhile Mike finds himself falling for a much, much older woman who is a Supreme Court Justice.

It's Viva Las Vegas for Gary and Mike, when Mike forms a plan to help Gary get rid of his "virginitis" by setting an unknowing Gary up with an escort. Gary thinks the girl really likes him and winds up falling for her hard. Meanwhile Mike is counting cards in the casino owned by the same honked-off mobsters who gave them their hotel room, as his source of income.

Gary and Mike are in The Big Apple, New York, and their car gets stolen; so they decide to disguise themselves as Jews and go to a bar mitzvah. Some other Jewish people chase them down to the subway. Gary and Mike have an argument and separate, and Gary becomes one of the "Mole People" who live in the sewers while Mike seems to luck out at every turn from being handed $50 by a generous blind man, to getting to model with European supermodels, to bedding with them. Presumably after they reunite and reconcile, they would head to Atlantic City, New Jersey, as mentioned. However, this was not made into an episode.

While making their way to Chicago, Illinois, Gary has the inside of his mouth stung by a bee and is rushed to a hospital. After a close call with death, Gary soon decides he should come clean with his father about his road trip with his buddy Mike and breaks the news to him on a special Father's Day episode of "Jerry".

In Hollywood, California, the guys attempt to party with the celebrities. They elude an oversexed TV mother and then encounter a strangely compliant person who might be Gwyneth Paltrow.

Between Minneapolis and St. Paul, Minnesota, the duo make their way to the Mall of North America (a parody of Mall of America) to spend a large amount of coupons to support themselves for the whole winter...only to discover that the coupons have expired (the coupon book turned out to be sold to Mike by an ex-con who conned Mike into buying it). Through the kindness of a corn dog business owner (played by Stacy Keach), Gary and Mike get a job at Corn Diggity Dog in the Mall. A competitor corn dog company called Porn Dog is putting Corn Diggity Dog out of business until Gary realizes he can save the business by winning a trick Corn Dog competition.

In San Francisco, California Officer Dick finally manages to catch up with the duo again, and pursues them in a high-speed chase. However, like his last two attempts, his efforts would end in vain. After Dick lands into a gay bar, both of them run over a speed-bump, causing Mike to spill his Slurpee on the Marine Corps flag Gary bought for his dad, as well as his shirt. Mike then prompts Gary to take off his shirt and dry it off in the breeze along with the flag. Little do the two of them know that they are driving in front of a Gay Pride Parade on national television which Mr. Newton sees, and mistakenly assumes that Gary is gay and Mike is his partner. After Gary's dad signs him up for the Marines, he goes to a strip club and meets a mysterious stranger, Jared, (voiced by Tim Curry) who tells him he will kill Gary's dad; if Gary kills the stranger's wife. After the wife dies accidentally, Gary must race to save his father's life. However upon stopping Jared, he tells the police Gary killed his wife and then him (after Gary accidentally makes Jared get a lethal injection). They are then chased by the Police themselves and are cornered at an incomplete highway. Gary in turn, feeling trapped by his dad with nowhere to go but down, then tells Mike to make the suicidal jump. The episode ends with a fade to white with the caption "To Be Continued..."   According to co-creator Adam Small, the duo was scripted to survive by landing in the water or something else. 10 more episodes were planned and fully developed for a second season but never saw production on account of the circumstances surrounding the show's cancellation.