The purpose of this study is to examine racial/ethnic and gender variations and intersectionality in the knowledge, attitudes, intentions, and behaviors pertaining to substance abuse (SA) and human immunodeficiency virus (HIV)/sexually transmitted disease (STD) prevention among racial/ethnic minority college students (ages 18-24) in South Texas. A total of 535 minority students completed a baseline survey between 2014 and 2016 (N = 535). Results revealed statistically significant (ranging from p < .05 to p < .001) racial/ethnic and gender variations in SA and HIV/STD prevention-related knowledge, attitudes, intentions, and behaviors. However, the significant interaction effects (i.e., intersectionality) were observed only for two of the nine composite variables. That is, although male minority students exhibited lower levels of awareness of sexual risks and safe sex negotiation skills than female minority students, Hispanic male students appeared to fare better in both awareness of sexual risks (p < .01) and safe sex negotiation skills (p < .05) compared to students of other racial/ethnic origin. Implications for prevention and intervention work involving minority college students are discussed.