In 1989, when he was 12 years old, a Bisaan abducted his brother Matty when they went fishing on a creek. For many years he told people about the strange creature that abducted Matty, however Sheriff Cochran who investigated the case hid the truth about it and covered it in order to cover his daughter's actions and involvement in the incident. This made the case remain abandoned throughout the next 27 years.
At some point, he began hunting to get revenge for his brother. In 2009, he began work together with his husband, Cesar. They operated from Mexico to Texas since then. When they realized that the Bisaans are going to return in 2016 to attack people at Jesse's home town, they returned from their operating area to end the Bisaan problem forever.
When Dean tracked down an impregnated Libby in the forest, he got ambushed by a male Bisaan. Dean nearly lost the brawl, but thanks to Cesar's assistance, the Bisaan was decapitated. Jesse later arrived and stabbed the Bisaan's torso multiple times just to make sure that the creature was really dead.
They later shared their knowledge about Bisaan with the Winchester and how to deal with them. He then teamed up with Sam to track down the formal sheriff Cochran to question him about what really happened 27 years ago. When he realized that everything Cochran did was to keep his daughter's actions hidden, Jesse was outraged. Cochran then revealed the location of the Bisaan lair. When they arrived there, they found Dean and Cesar preparing to burn the place down. They later found the corpse of Matty and others that fell victim to the Bisaan. After locating them, they gave the proper hunter funeral pyre rite to all of the fallen victims and destroyed the Bisaan lair.
In the aftermath, the Cuevas later retired from hunting and returned to their home in New Mexico to breed horses.