Objective. The influence of religion, acculturation, and incarceration on substance abuse has been studied, though predominantly among adolescents. Little research exists on how such factors influence substance use among Hispanic adults. The objective of this study was to assess key determinants of substance use among Hispanic adults. Methods. Public access 2012 National Survey on Drug Use and Health was utilized. Univariate and multivariable logistic regression analyses were conducted while accounting for complex survey design to obtain population-weighted estimates. Receiver operator curve analysis was used to evaluate the relative contribution of each variable. Results. Importance of religious influence in life and Spanish language interview were associated with lower odds of substance use, while history of incarceration increased the likelihood of substance use among Hispanic adults. Other factors associated with lower odds were increasing age, being female, and currently married. Other factors associated with increased odds were high school graduate and some college in addition to living above the 200% federal poverty level. Discussion. Results from this study add to the limited body of the literature on determinants of substance use among Hispanic adults. Health education measures should target acculturated Hispanic adults and those with incarceration history to reduce substance use.