BACKGROUND: The present study aims to (1) identify classes of psychosocial syndemics among adolescents in the U.S. based on psychological factors, such as depression and suicidal ideation, and social factors, such as binge drinking, alcohol use, and drug use; (2) identify correlates of psychosocial syndemics; and (3) examine the independent associations between psychosocial syndemic factors and sexual risk practices. METHOD: We used latent class analysis and a sample of 14,762 U.S. high school students who participated in the 2017 Youth Risk Behavior Surveillance System to examine youth population profiles based on shared characteristics of syndemics. Adjusting for sociodemographic factors, we conducted logistic regression to explore the connections between psychosocial syndemic factors and three sexual risk practices, namely, early initiation of sexual intercourse, condom use, and sex with multiple partners. RESULTS: The study results indicate that three classes of risk exist among the sample: substance misuse (class 1, n = 3872, 26.2%), normative (class 2, n = 8791, 59.6%), and mental health problems (class 3, n = 2099, 14.2%). Class membership of psychosocial syndemics was significantly different by gender, age group, and race. The odds of initiating sexual intercourse before age 13 were positively associated with participants belonging in the substance misuse class and the mental health problem class. The odds of using condoms during the last sexual intercourse for currently sexually active adolescents were lower for participants classified in the substance misuse class. The likelihood of reporting having sex with four or more partners in a lifetime was higher among participants belonging to the substance misuse class. CONCLUSION: The study advances our understanding of the heterogeneity of class membership associated with psychosocial syndemic risk factors among adolescents and extends our understanding of syndemics in the area of adolescent health. Thus, practitioners and policymakers can design multicomponent and multilevel school-based HIV/STI prevention programs that meet the needs of adolescents.