Although over 70% of American Indians and Alaska Natives (AI/ANs) reside in urban areas, our knowledge of urban AI/AN adults receiving mental health treatment is limited. This study compares primary psychiatric diagnoses, commercialized tobacco use, and homelessness between AI/AN and non-AI/AN adults receiving services in an urban public mental health agency serving primarily AI/AN people in southern California. Depressive disorders were the most common psychiatric diagnoses for both groups. However, AI/AN adult clients demonstrated significantly less anxiety disorders and significantly more homelessness. Schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, and commercialized tobacco use were higher among AI/AN adults compared to non-AI/AN adults. Results from this study offer data needed to further understand important public health issues that exist among AI/AN adults receiving mental health services in urban areas. We provide suggestions to enhance integrated and culturally appropriate treatment approaches and homelessness initiatives for this under-resourced, yet resilient population.