BACKGROUND Homelessness is associated with high prevalence of psychiatric disorders such as substance use disorders, including alcohol use disorder, and depression. METHODS This case series and feasibility trial evaluated a novel integrated cognitive behavioral treatment (ICBT), which was adapted specifically for homeless individuals and developed to treat substance use and depressive symptoms simultaneously. The ICBT was delivered among four homeless individuals enrolled in the Treatment First program (a social services program where treatment is offered in conjunction with temporary transitional housing), who had access to stable and sober housing milieus. RESULTS The ICBT was rated high in expectancy of improvement, credibility, and satisfaction, with few treatment-related adverse events, and fairly high treatment retention. At 12 months follow-up, three of four participants were not homeless anymore. Some participants experienced short-term reductions in substance use and/or depressive symptoms. CONCLUSIONS The study provided preliminary support that the ICBT can be a feasible and potentially effective treatment for homeless individuals with substance use and/or depressive symptoms. However, the delivery format within the Treatment First program was not feasible. The ICBT could be offered within the social services Housing First program instead (where permanent housing is offered before treatment), or to non-homeless individuals. BACKGROUND The study was registered retrospectively at ClinicalTrials.gov (NCT05329181).