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OBJECTIVES Discrimination has been shown to have profound negative effects on mental and behavioral health and may influence these outcomes early in adulthood. We aimed to examine short-term, long-term, and cumulative associations between different types of interpersonal discrimination (eg, racism, sexism, ageism, and physical appearance discrimination) and mental health, substance use, and well-being for young adults in a longitudinal nationally representative US sample. METHODS We used data from 6 waves of the Transition to Adulthood Supplement (2007–2017, 1834 participants) of the Panel Study of Income Dynamics. Outcome variables included self-reported health, drug use, binge drinking, mental illness diagnosis, Languishing and Flourishing score, and Kessler Psychological Distress Scale score. We used logistic regression with cluster-robust variance estimation to test cross-sectional and longitudinal associations between discrimination frequency (overall, cumulative, and by different reason) and outcomes, controlling for sociodemographics. RESULTS Increased discrimination frequency was associated with higher prevalence of languishing (relative risk [RR] 1.34 [95% CI 1.2–1.4]), psychological distress (RR 2.03 [95% CI 1.7–2.4]), mental illness diagnosis (RR 1.26 [95% CI 1.1–1.4]), drug use (RR 1.24 [95% CI 1.2–1.3]), and poor self-reported health (RR 1.26 [95% CI 1.1–1.4]) in the same wave. Associations persisted 2 to 6 years after exposure to discrimination. Similar associations were found with cumulative high-frequency discrimination and with each discrimination subcategory in cross-sectional and longitudinal analyses. CONCLUSIONS In this nationally representative longitudinal sample, current and past discrimination had pervasive adverse associations with mental health, substance use, and well-being in young adults.