Somewhere in a jungle, a terrified woman is being chased by some tribesmen. She is caught and thrown into a pit of snakes that repeatedly bite her, until a giant python slithers into her mouth. Elsewhere, Richie Gecko breaks his brother Seth out of jail and the two set off on a crime spree. They rob a bank, killing four Texas Rangers and two police officers in the process, and stop at Benny's World of Liquor. Rangers Earl McGraw and Freddie Gonzalez arrive and a bloody standoff ensues. Richie has visions of demons and a mysterious woman beckoning him from beyond, and Seth learns from the drug-lord Carlos that the Geckos must reach the Mexican border on their own.
Following their escape from the liquor store, the Geckos discuss recent events, including taking a teller hostage from the Abilene bank robbery. Richie's visions continue, causing Seth to think he is unstable. Although taken off the case, Ranger Gonzalez continues pursuing the Geckos, thinking one of them has killed drug cartel members. Meanwhile, six months after a car accident claimed his wife's life, Jacob Fuller takes his family on a vacation. His daughter Katie believes it to be something more. She remains in contact with her boyfriend, Kyle, who ends up being killed by Carlos, now seen as a vampire. As Kyle, Carlos reveals Jacob to be a minister who has lost his way.
The Geckos and their hostage stop at the Dew Drop Inn. Seth goes to get some food at Big Kahuna Burger and meets his wife to tell her that plans have changed. Even though she has helped them in the past, she should cross the border alone. Back in the motel room, Richie's seductive visions cause him to kill the bank teller. Meanwhile, the Fullers' RV breaks down near a bar where Gonzalez meets a professor who explains the Mesoamerican symbols he has found. The professor speaks of a "blood cult" that we see Carlos is a part of and that Richie is trying to understand.
The Geckos', the Fullers' and Gonzalez's paths merge at the Dew Drop Inn. Seth decides that the Fullers and their RV are the Geckos' ride across the border. Alone with Katie, Richie can sense something about her father is bothering her. Although curious, she is uneasy with this, as she has learned her father and mother might have argued in the car just before the fatal accident. Gonzalez, in possession of Richie's symbolic knife, begins to have visions of a man killed during his first Ranger bust with Earl. After a shootout with the police and Gonzalez, the Geckos and Fullers escape in the RV.
The RV reaches the Mexico border, but must wait its turn in line to pass through border patrol. Richie fears the Fullers, as he believes Jacob is a demon. Jacob finally explains to his children about the car accident that killed their mother and caused him to lose faith in God. Meanwhile, Gonzalez escapes detention to arrive at the border, only to be held by Carlos, who has taken the form of the chief border agent and allows the RV to enter Mexico. The RV arrives at the Titty Twister bar.
Gonzalez crosses into Mexico and is captured by Carlos's cartel. Carlos wants him tortured and killed, after hearing he has insight about the blood cult. At the Titty Twister, Seth believes they made a mistake coming there, while Richie believes otherwise. Outside, a man named Narciso saves Seth from a biker gang attack led by the bar's bouncer. Gonzalez escapes the cartel and arrives at the bar, just in time for Carlos to introduce Santanico Pandemonium's show. Richie recognizes her as the woman in his visions that led him there.
Santanico performs a sultry dance for the audience before climbing onto the Geckos' and Fullers' table. Gonzalez uses her dance as a distraction to pin Richie's hand to the table with a knife. This causes Santanico and others to transform into serpentine vampires. They attack most everyone in the bar, as Carlos and the blood cult members briefly watch then move to a back room. The Geckos and Fullers survive the attack, but know there will be more when they find the bar sealed shut. Professor Tanner, known there as "Sex Machine", informs them of the mythology of the bar/temple. Meanwhile, in the back room, Carlos and Santanico dispose of the nine cult members who call them "slaves". Santanico returns to the bar for Richie and another attack begins.
As Santanico tries to turn Richie to her cause, Freddie confronts Carlos about his destiny and the temple’s mysterious past. Seth, the Fullers and Sex Machine battle their way deeper into the temple, where they meet an unexpected ally.
Venturing further into the temple below the bar, everyone mostly gets separated from each other. Scott helps Carlos in a fight with Gonzalez, after Carlos turns Scott. Richie gets turned by Santanico but must help Seth pass a test inside a mental labyrinth, where faces from their page pop up in unexpected places, wherein they also reenact the robbery that led to Seth's imprisonment. During the test, Seth learns Richie killed their father, when they were kids, by setting him on fire. Tanner helps Kate through the temple, after she witnesses her mother overdosing on sleeping pills and her father wrecking the car rushing her to the hospital. Tanner leads Kate to a sacrificial room, hoping to appease the Gods of the culture he has studied all these years.
Freddie realizes Aiden is a cult fanatic and saves Kate by killing him. Alone with Scott, Jacob cannot bring himself to kill his son who has turned, while Scott bites his father, hoping Jacob will see that being a demon serves a better purpose. Kate must kill her father before he turns. The Geckos survive their test, but Richie swallows the serpent containing Santanico's blood, making him her prince. Carlos betrays her by siding with Narciso and the Nine Lords. He kidnaps Richie, wanting Seth to bring him the $30 million in oil bonds. A final battle ensues, before the sun rises to cleanse the bar/temple of its cult. Freddie is allowed to return to his family, Richie and Santanico head for the States, Carlos is welcomed into the Nine, and Seth and Kate ride off together.
Three months after freeing Santanico from the Titty Twister, the Gecko Brothers are still on the run. Seth and Kate are lost in Mexico, while Richie and Santanico plot vengeance on the culebra Lord who imprisoned her.
Seth and Kate pull off a heist, while Ranger Freddie Gonzalez confronts nightmarish visions that lead to a gruesome discovery. Back at the Twister, Carlos’s emergence from the Labyrinth sets Malvado’s plans into motion.
Richie (Zane Holtz) and Santanico (Eiza González) pose as sex traffickers to infiltrate Malvado’s (Esai Morales) food supply, while Sonja (Briana Evigan) forces Seth (D. J. Cotrona) to kick his drug habit. Meanwhile, Freddie (Jesse Garcia) faces off with Sex Machine (Jake Busey), who attacks his family to retrieve the codex.
Kate (Madison Davenport) hunts down Scott (Brandon Soo Hoo) in Bethel before he can exact revenge. In Houston, Richie (Zane Holtz) and Santanico (Eiza González) find themselves deep in the flesh trade, while Seth (D. J. Cotrona) tries to get back in Uncle Eddie’s (Jeff Fahey) good graces.
Richie (Zane Holtz) and Seth (D. J. Cotrona) call a truce and work together to find Malvado’s (Esai Morales) headquarters. Carlos (Wilmer Valderrama), unhinged from the Labyrinth, abducts Santanico (Eiza González) and claims her for himself. And Kate (Madison Davenport) enlists Freddie’s (Jesse Garcia) help as she attempts to save her brother (Brandon Soo Hoo).
Following the trail of the mass grave, Freddie (Jesse Garcia) and Kate (Madison Davenport) uncover epic secrets and confront Oculto, a reclusive and dangerous Lord. Seth (D. J. Cotrona) and Richie (Zane Holtz) take the girls on a double date, and Carlos (Wilmer Valderrama) lets go of the past.
Uncle Eddie (Jeff Fahey) helps Richie (Zane Holtz) and Seth (D.J. Cotrona) make a plan to complete Santanico's revenge. Meanwhile, Freddie (Jesse Garcia) and Kate (Madison Davenport) encounter an unexpected foe following Malvado's (Esai Morales) attack.