Alcohol, tobacco, and other drug use pose serious health problems on college campuses. A significant body of research shows student religiosity to be a protective factor, but a very little research has examined influences of sexual identities on alcohol and other drug use among college students, and its associations with religious or spiritual identity. This study examined the relationships of sex/gender, sexual identity, and religious/spiritual identity on current alcohol use, drug use, and smoking via an online survey of 2,204 college students. We found a three-way interaction between sex/gender, sexual identity, and religious/spiritual identity, with religion showing protective value for nonheterosexual women, but not nonheterosexual men, related to alcohol use. Nonheterosexual students also showed different patterns of risk and protective factors. A subset of the sample that indicated that they did not use sexual identity labels showed very high rates of alcohol, tobacco, and drug use, often exceeding the lesbian, gay, and bisexual group on these measures. These findings provide new information on nonheterosexual student drug and alcohol use and indicate the need for additional research in this area of study.