This song tells the story of a jealous ex-boyfriend who is planning to take revenge on the man who stole his girlfriend. The man mentions using violent force as he speaks of "popping a cap in Sancho" and "putting that barrel straight down Sancho's throat". The lead singer of Sublime, Bradley Nowell, refers to the man as "sancho" and his ex-girlfriend as "heina". In Mexico, a man who steals another man's girlfriend is often referred to as "sancho" and a man's woman or girlfriend is referred to as "heina", which is adapted from the Spanish word "reina", meaning queen in English.
A music video was filmed in 1997 after the death of lead singer Bradley Nowell, who makes a cameo via stock footage. During the video, his beloved Lou Dog is seen along with the other members of Sublime remembering him. The video was a visualization of the story told in the song in the form of a Western, and featured Tom Lister, Jr. as Sancho. "Santeria" was a moderate U.S. crossover hit in the spring of 1997, cracking the Top 5 on Billboard's Modern Rock Tracks chart as well as reaching #43 on the Hot 100 Airplay chart. It is also a playable track on the 2008 video game Guitar Hero World Tour, and was released as a downloadable song for Rock Band 3 in 2012. The song was featured in the movie This is 40.