BACKGROUND AND OBJECTIVES Psychological empowerment, referring to one’s agency, self-efficacy, and meaningful participation in society, supports positive social and behavioral outcomes in adolescence; however, research examining psychological empowerment in the context of health remains limited. We sought to describe relationships between psychological empowerment and aspects of adolescents’ mental and physical health. METHODS School-based surveys were administered across 17 high schools in Allegheny County, Pennsylvania. We measured psychological empowerment with items adapted from a validated instrument. Health-related measures included past-year depressive symptoms, lifetime substance use, and measures of overall health and receipt of health care. Multilevel regression models examined associations between psychological empowerment and each health-related measure. RESULTS Among 3685 youth, the majority (n = 3391; 92.0%) were aged 14 to 17 years. Most were white (n = 1737; 47.1%) or Black/African American (n = 1166; 31.6%). Many identified as gender/sexual diverse (n = 1397; 37.9%). Youth with high psychological empowerment were less likely to report hopelessness (adjusted odds ratio [aOR], 0.61; 95% CI, 0.50–0.75), nonsuicidal self-injury (aOR, 0.57; 95% CI, 0.44–0.73), and suicidal ideation (aOR, 0.56; 95% CI, 0.42–0.75). Psychological empowerment was inversely associated with lifetime use of e-cigarettes (aOR, 0.70; 95% CI, 0.56–0.86), alcohol (aOR, 0.75; 95% CI, 0.61–0.92), and marijuana (aOR, 0.77; 95% CI, 0.62–0.94). Psychological empowerment was additionally linked to positive perception of health (aOR, 1.72; 95% CI, 1.29–2.31), receipt of preventive care (aOR, 1.26; 95% CI, 1.02–1.55), and less foregone care (aOR, 0.76; 95% CI, 0.61–0.94). CONCLUSIONS Findings underscore the importance of psychological empowerment as a modifiable protective factor in adolescence, particularly in youth-facing interventions focused on health and well-being.