Cocaine Use Disorder (CUD) is a significant public health problem associated with elevated morbidity and mortality within the United States. Current behavioral treatments have limited efficacy and there are currently no FDA approved pharmacological treatments for CUD. Classic psychedelics might be associated with lowered odds of substance misuse and may effectively treat various forms of addiction. Thus, the goal of this study is to assess protective associations that lifetime use of classic psychedelics may share with CUD within a nationally representative sample of the U.S. We used data from The National Survey on Drug Use and Health (NSDUH) (2015–2019) and conducted survey-weighted multivariable logistic regression to test whether each of four classic psychedelics (peyote, mescaline, psilocybin, LSD) conferred lowered odds of CUD and its related 11 sub-criteria. Participants were 214,505 adults in the NSDUH (2015–2019) aged 18 and older. Peyote conferred lowered odds of CUD, reducing the odds of CUD by over 50% (aOR: 0.47). All other substances (including other classic psychedelics) either shared no association to CUD or conferred increased odds of CUD. Furthermore, sensitivity analyses revealed peyote to confer sharply lowered odds of the majority (seven of 11) of CUD criteria as well (aOR range: 0.26–0.47). Peyote use is associated with lowered odds of CUD. Future inquiries into third variable factors (i.e., demographic/personality profiles of individuals who use peyote, motivational/contextual factors surrounding peyote use) that may underlie our observed associations may reveal protective factors that can inform treatment development for CUD. Additionally, future longitudinal studies can shed further light on whether there is a temporal link between peyote use and lowered odds of CUD.