ABSTRACT Psychedelic use has been increasingly accepted socially and legally. However, there is a gap in understanding how religion can influence the relationship between psychedelics and mental health. This study aims to explore this relationship by examining the impact of lifetime classic psychedelic use (LCPU), religious attendance, and religious salience on monthly psychological distress, using the K6 scale. The data for this project is sourced from the National Survey of Drug Use and Health (NSDUH) from 2008 to 2019, with a sample size of 458,372. The analysis utilizes several Ordinary Least Square regression models conducted in Stata 17. The results indicate that both religion and psychedelic use are associated with lower levels of psychological distress. While increased religious salience is linked to reduced distress, this effect is weakened by psychedelic use, as higher salience is associated with higher levels of distress among individuals who have used psychedelics. However, a three-way interaction analysis reveals that individuals with high religious salience and attendance experience the lowest levels of distress.