We sought to estimate the prevalence of lifetime psilocybin use among a national sample of US adults ages 18 and older and associated demographic/substance use correlates. Pooled data from the 2015–2018 National Survey on Drug Use and Health were utilized among 168,650 individuals 18 years or older. An estimated 9.68% of individuals reported lifetime use of psilocybin. Differences were found among demographics, drug use, and sexual identity, with bisexual identification being associated with greater lifetime use. Nearly two-thirds of individuals who have ever used Lysergic acid diethylamide (LSD), methamphetamine, and/or heroin also reportedly used psilocybin. Findings from the present study can inform harm reduction efforts and behavioral health messaging.