Youth experiencing homelessness have been shown to experience high levels of both trauma and substance use. However, prior work has yet to consider how substance use, posttraumatic stress disorder (PTSD) symptoms, and homelessness are temporally, or reciprocally, associated over time. The current study uses symptom-driven and experience-driven models to examine the reciprocal relationships between substance use, PTSD symptoms, and homelessness among a large sample of adolescents receiving substance use treatment in the United States. Adolescents (n = 20,069; Mage = 15.6; 74% male) completed baseline, 3-, 6-, and 12-month assessments. Autoregressive latent trajectory with structured residual (ALT-SR) models were used to examine within- and between-person relationships. We found continued support for prior work at the between-person level of analysis. At the within-person level, during the treatment phase, PTSD emerged as a key mechanism predicting both return to use and increased days of homelessness posttreatment. Further, greater substance use at treatment completion was associated with greater PTSD symptoms and homelessness, prospectively. The current study extends the previous work to consider individual level processes in conjunction with overarching event level predictors of homelessness. We found that PTSD symptomology is a driving factor that influences, both directly and indirectly, experiences of homelessness posttreatment. Interventions may wish to incorporate trauma informed approaches for youth entering treatment as this may mitigate long-term experiences of homelessness and return to substance use.