Opioid use disorder (OUD) is a major source of morbidity and mortality in the U.S. and there is a pressing need to identify additional treatments for the disorder. Classic psychedelics (psilocybin, peyote, mescaline, LSD) have been linked to the alleviation of various substance use disorders and may hold promise as potential treatments for OUD. The aim of this study was to assess whether the aforementioned classic psychedelic substances conferred lowered odds of OUD. Furthermore, this study aimed to replicate and extend findings from Pisano et al. (2017) who found classic psychedelic use to be linked to lowered odds of OUD in a nationally representative sample. We used recent data from the National Survey on Drug Use and Health (2015–2019) (N = 214,505) and multivariable logistic regression to test whether lifetime use (yes/no) of classic psychedelics was associated with lowered odds of OUD. Lifetime psilocybin use was associated with lowered odds of OUD (aOR: 0.70; 95% CI [0.60, 0.83]). No other substances, including other classic psychedelics, were associated with lowered odds of OUD. Additionally, sensitivity analyses revealed psilocybin use to be associated with lowered odds of seven of the 11 DSM-IV criteria for OUD (aOR range: 0.66–0.83). Future clinical trials and longitudinal studies are needed to determine whether these associations are causal.