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Background A four- to seven-fold increase in the prevalence of current mood, anxiety, substance use and any mental disorders in Indigenous adults compared with non-Indigenous Australians has been reported. A lifetime prevalence of major depressive disorder was 23.9%. High rates of comorbid mental disorders indicated a transdiagnostic approach to treatment might be most appropriate. The effectiveness of psychological treatment for Indigenous Australians and adjunct Indigenous spiritual and cultural healing has not previously been evaluated in controlled clinical trials. Aims This project aims to develop, deliver and evaluate the effectiveness of an Indigenous model of mental healthcare (IMMHC). Trial registration: ANZCTR Registration Number: ACTRN12618001746224 and World Health Organization Universal Trial Number: U1111-1222-5849. Method The IMMHC will be based on transdiagnostic cognitive–behaviour therapy co-designed with the Indigenous community to ensure it is socially and culturally appropriate for Indigenous Australians. The IMMHC will be evaluated in a randomised controlled trial with 110 Indigenous adults diagnosed with a current diagnosis of depression. The primary outcome will be the severity of depression symptoms as determined by changes in Beck Depression Inventory-II score at 6 months post-intervention. Secondary outcomes include anxiety, substance use disorder and quality of life. Outcomes will be assessed at baseline, 6 months post-intervention and 12 months post-intervention. Results The study design adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement recommendations and CONSORT extensions for pilot trials. We followed the Standard Protocol Items for Randomised Trials statement recommendations in writing the trial protocol. Conclusions This study will likely benefit participants, as well as collaborating Aboriginal Medical Services and health organisations. The transdiagnostic IMMHC has the potential to have a substantial impact on health services delivery in the Indigenous health sector.