BACKGROUND: Efficiency refers the use of resources in ways that optimise desired outcomes. Health system efficiency is a priority concern for policy makers globally as countries aim to achieve universal health coverage, and face the additional challenge of an aging population. Efficiency analysis in the health sector has typically focused on the efficiency of healthcare facilities (hospitals, primary healthcare facilities), with few studies focusing on system level (national or sub-national) efficiency. We carried out a thematic review of literature that assessed the efficiency of health systems at the national and sub-national level. METHODS: We conducted a systematic search of PubMed and Google scholar between 2000 and 2021 and a manual search of relevant papers selected from their reference lists. A total of 131 papers were included. We analysed and synthesised evidence from the selected papers using a thematic approach (selecting, sorting, coding and charting collected data according to identified key issues and themes). FINDINGS: There were more publications from high- and upper middle-income countries (53%) than from low-income and lower middle-income countries. There were also more publications focusing on national level (60%) compared to sub-national health systems' efficiency. Only 6% of studies used either qualitative methods or mixed methods while 94% used quantitative approaches. Data envelopment analysis, a non-parametric method, was the most common methodological approach used, followed by stochastic frontier analysis, a parametric method. A range of regression methods were used to identify the determinants of health system efficiency. While studies used a range of inputs, these generally considered the building blocks of health systems, health risk factors, and social determinants of health. Outputs used in efficiency analysis could be classified as either intermediate health service outputs (e.g., number of health facility visits), single health outcomes (e.g., infant mortality rate) or composite indices of either intermediate outputs of health outcomes (e.g., Health Adjusted Life Expectancy). Factors that were found to affect health system efficiency include demographic and socio-economic characteristics of the population, macro-economic characteristics of the national and sub-national regions, population health and wellbeing, the governance and political characteristics of these regions, and health system characteristics. CONCLUSION: This review highlights the limited evidence on health system efficiency, especially in low- and middle-income countries. It also reveals the dearth of efficiency studies that use mixed methods approaches by incorporating qualitative inquiry. The review offers insights on the drivers of the efficiency of national and sub-national health systems, and highlights potential targets for reforms to improve health system efficiency.