An animated comedy about two culturally and ethnically different families who live next door to each other near the U.S.-Mexican border begins with border guard Bud furious about learning his daughter is engaged to J.C., a young Latino man who is a recent college graduate. To Bud's delight, however, is news that a new anti-immigration law may get J.C. deported.
Bud's reverend wants him to lure Ernesto, the Mexican Catholic Church's biggest donor, over to their denomination, and Ernesto is taken by the glitzy place of worship. This leads the reverend to recruit other Mexican parishioners into his flock and sends Bud into a holy uproar.
Bud becomes the high school football coach after the previous coach is forced out of the job by the local redneck fans. Bud, desperate to win, discovers a secret weapon - an illegal immigrant whom he sees gracefully and skillfully run across the border. Of course, this kid also happens to be the No. 1 drug mule in Mexico.
As Bud and Janice prepare to consummate their yearly anniversary sex, Maria's sister has a baby, which tips the Mexifornia population from white majority to Latino majority. So, Bud decides he needs to have a baby to counteract the number shift.
Ernesto attempts to get J.C. into the "real world" by forcing him to work on his crew. J.C. is appalled at what he believes are terrible working conditions and goes on strike, causing a rift in the Gonzalez family and in J.C.'s relationship with Becky. Meanwhile, Bud is stalked by an ostrich that he decides is his "spirit animal".
The Santa Ana winds bring on a series of strange events in Mexifornia: In search of a new energy drink, Sanford travels to Mexico and gets hooked on a new, even more powerful elixir; Bud helps a Mexican "Bud" look-alike sneak over the border, so he can take a break from his own life; and Ernesto is tormented by a stubborn demon leaf which even his super-powerful leaf blower cannot remove.
Gert's unhealthy eating causes her to have a heart attack during the Little Miss Mexifornia Pageant. Unable to afford the surgery in America, Bud takes her to Mexico to have her arteries unblocked and heart repaired. Meanwhile, Ernesto and Maria put Pepito on medication that makes him behave, but they don't like the side effects.
When a wildfire threatens Mexifornia, all residents are required to evacuate. However, Bud refuses to leave his house, which catches fire, and Ernesto must comes to the rescue to save him. Meanwhile J.C. and Becky decide to take a break from their relationship and see other people in order to explore what it's like to date before committing to each other.
Ernesto and Placido are thrilled that their favorite TV show, "La Fiesta Noche," will be filming in Mexifornia. The Buckwalds and Gonzalezes both get tickets to the taping, but Bud's anger at the spectacle causes him to be called onto the stage. Much to everyone's surprise, the audience loves him and he becomes a big star in the Mexican community.
At Gert's insistence, Janice secretly spends $285 on an American Gal doll. When she maxes out the credit card out on accessories, she's forced to get a job as Ernesto's housekeeper, and Bud schemes to get her fired. Meanwhile, Gert seeks revenge against the American Gal company.
When the Department of Homeland Security moves El Coyote to the #1 spot on its "Most Wanted" list, Bud and Barracuda both set out to catch him. Bud wants to catch he so he can keep his job, because he inadvertently let him over the border. Barracuda wants to catch him to reclaim the top spot on the list. Meanwhile, Ruiz sets out to free El Coyote in an attempt to appear "more Mexican" to a pretty waitress.