With increasing recognition of the importance of mental and substance use disorders for population health and health systems and the potential value of systems-based performance indicators in addressing this issue, we aimed to describe the development and content of key performance indicators for mental and substance use disorders. Publications were identified through official websites, Google searches and PubMed. Following ‘PRISMA’ guidelines, twenty-five studies were kept for qualitative synthesis and six for quantitative analysis. We describe their use in practice by comparing their application across a range of public and mixed healthcare systems. Currently, key performance indicator development for mental and substance use disorders adopts several methodologies, including expert opinion, literature review, stakeholder consultation and the structured consensus method. The rationales provided for selection of particular key performance indicators vary greatly between systems. Systems exhibit different levels of key performance indicator adaptability, which is reflective of dynamic changes in evidence-based practices. We noted bias in the level of key performance indicator assessment towards system/health plan evaluation followed by programme/service evaluation. Similarly, there is a large skew towards key performance indicators that reflect evaluation of processes. Collection of data in all systems is nearly exclusively reliant on electronic administrative/medical data. Experiences from these systems are synthesized into methodological recommendations, and considerations for further research and clinical practice are provided.