Objective: The aim of this study was to systematically review the evidence-base for the effectiveness of culturally unadapted, culturally adapted and culture-based interventions for Indigenous adults with mental or substance use disorders. Methods: We conducted a systematic search of scientific databases, government websites and web-based Indigenous research repositories. We sought studies using designs comparing an intervention group to a control/comparator group or pre- and post-test designs, published between 2000 and 2015 examining interventions to improve individual-level outcomes (e.g. remission, symptoms, quality of life, functioning) or service-level outcomes (e.g. number of interventions delivered) for Indigenous adults with mental or substance use disorders in Australia, Canada, New Zealand or the United States. Results: A total of 16 studies met inclusion criteria. Virtually all North American studies (6 US and 1 Canadian) evaluated culturally unadapted interventions, all of which were interventions for substance use. Two-thirds of Australian and New Zealand studies evaluated culturally adapted interventions and included samples with mental disorders. Of eight culturally unadapted psychological/psychosocial, pharmacological and educational intervention studies, seven reported significant improvements on at least one measure of psychological well-being, mental health problem severity, or significantly reduced alcohol or illicit drug use. Of seven culturally adapted psychological/psychosocial intervention studies, all reported significant improvement on at least one measure of symptoms of mental illness, functioning, and alcohol use. One culture-based psychological/psychosocial intervention study significantly reduced problem severity in medical and psychiatric domains. Conclusion: There remains inconclusive evidence regarding interventions due to a small and methodologically weak evidence-base. The literature would be enhanced by intervention replication and outcome standardisation, validating the outcome instruments used in Indigenous populations, including sample size calculations and using stronger research designs (e.g. interrupted time-series designs). Robust implementation and outcomes research is needed to further progress evidence-based practice in Indigenous mental health.