Adolescents are often the most vulnerable to risky behaviors due to their quest for independence, experimentation, and identity development, resulting in deep-rooted patterns that affect health across the life course. This review examines the prevalence and determinants of substance use and sexual risk behaviors among adolescents in the United States. A systematic search of peer-reviewed literature published between 1980-2023 was conducted using multiple databases. Studies focusing on U.S. adolescents aged 12-19 and reporting on prevalence or associated factors of substance use (alcohol, tobacco, marijuana, or any illicit drugs) or sexual risk behaviors (early sexual initiation, multiple partners, or inconsistent condom use) were included. The review synthesized data from 40 studies meeting inclusion criteria. Results indicate concerning rates of substance use and sexual risk-taking, with variations by demographic factors. Alcohol and marijuana use were most prevalent, reported by 30-40% of adolescents. Nearly half of high school students reported having sexual intercourse, with 40% not using condoms consistently. Prevalence was generally higher among older adolescents, sexual minorities, and some racial minority groups. Key determinants of risk behaviors were reviewed based on socioecological models including individual, interpersonal, community and societal factors. The review highlights the multilevel nature of influences on adolescent risk behaviors. Findings underscore the need for tailored interventions addressing multiple determinants. Particular attention to vulnerable groups such as African American Adolescents and social determinants of health inequities is warranted. More research on risk and protective factors and effective interventions is needed. This synthesis can inform the development of evidence-based policies and programs to reduce substance use and sexual risk behaviors among U.S. adolescents.