Purpose: Indigenous conceptions of health have been shown to differ from that of their non-Indigenous counterparts. As a result, there remains uncertainty over the appropriateness and value of using existing health-related quality-of-life (HRQoL) instruments in Indigenous communities. The objective of this review was to identify studies that either measure the HRQoL of an Indigenous population or validated a measure used to elicit the HRQoL in an Indigenous population. Methods: A systematic review of the published literature was conducted to (1) investigate the extent to which HRQoL instruments are used in Indigenous populations; (2) to identify which instruments have been validated in which populations; and (3) to identify which instruments have been tailored for use with Indigenous populations. Results: Forty-one studies were included in the review. Only three of the 41 studies utilised Indigenous-specific instruments. The remainder (38 studies) utilised generic population or disease-specific instruments. Four studies found specific HRQoL instruments to be valid in these populations and 32 estimated the HRQoL of an Indigenous population. The limited examples of Indigenous-specific instruments highlighted the potential importance to the HRQoL of these populations of domains that lie outside of traditional measures including social and community domains as well as domains relating to culture, diet and land use on top of more traditional HRQoL domains. Conclusion: Ensuring that the HRQoL of Indigenous populations is being appropriately measured is vital to prioritising available resources to the most effective interventions. HRQoL instruments present an opportunity to directly elicit and incorporate Indigenous preferences and conceptions of health into these decisions. Further work is required in the field to ensure that this potential is realised.