Trauma, depressive symptoms, and the use of alcohol and drugs are common among youth, especially those with marginalized racial/ethnic identities, sexual and gender minority youth (SGMY), and those with low socioeconomic status, homelessness, and HIV-positive status. However, most research on trauma, depression, and substance use among such youth is cross-sectional. This article examines these patterns over time. Participants were youth with multiple life challenges (N = 1,728) recruited from 13 community-based agencies and health centers in Los Angeles, CA, and New Orleans, LA, and reassessed twice at 4-month intervals over 8 months (follow-up > 70%). Youth were predominantly Black, Latiné, and SGMY, with an average age of 21 years (range 12-24). We analyzed the association between trauma, depression, and substance use using a Bayesian approach to latent growth curve modeling. Trauma had a robust, positive association with depressive symptoms and substance use, although this association differed depending on whether alcohol or cannabis use was examined. Higher levels of trauma were also associated with a slower decline in depressive symptoms over time. Study findings highlight the longitudinal association between trauma and both depression and substance use. This suggests the potential utility of trauma-focused interventions among vulnerable youth with one or both of these issues. (PsycInfo Database Record (c) 2024 APA, all rights reserved).