Children and adolescents (“youth”) experiencing homelessness are at a disproportionately high risk of exposure to potentially traumatic events (PTE). However, limited evidence exists as to what interventions are effective when implemented with this high-risk population. The purpose of this study was to (1) document the mental health and trauma-related needs of sheltered youth and their mothers, and (2) examine the feasibility/effectiveness of Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) administered within the context of a homeless shelter. Three hundred and twenty-one youth (Mage = 10.06 years, SD = 3.24 years, 56.4% male, 70.1% Black/African American, 34.6% Hispanic/Latinx) and their mothers were recruited from a homeless shelter and provided 10 weeks of TF-CBT, with the option for up to eight additional weeks of therapy based on clinical need. Families completed pre- and post-intervention assessments. Results demonstrated clinically elevated pre-intervention PTSD symptoms and rates of exposure to PTE in sheltered youth well above those previously reported in the general population. TF-CBT resulted in substantial reductions in both maternal and self-reported severity of youth PTSD symptomology, which were largely attributable to reductions in re-experiencing and arousal. Effectiveness of TF-CBT varied by age and the number of exposures to PTE. Overall, these findings illustrate the importance of assessing and addressing the mental health and trauma-related needs of sheltered youth and the feasibility and efficacy of embedding an evidence-based trauma-focused treatment protocol within a shelter environment. Additional implications of these findings are discussed.