An increasing number of health system researchers use systematic review to synthesize research evidence to inform the development of health policies at global and national levels. However, there are methodological challenges facing the health system research in undertaking systematic reviews of health policy literatures. This paper explored the constraints and promise of systematic review as a tool for evidence-based health system research in developing countries. It introduced the systematic review method and its evolution in health research over the past decades. The paper then discussed the definition of health system research, as system science, and contrasted its features/characteristics to those of medical research. It discussed and analyzed if the systematic review could be an effective tool for evidence-based health system research, particularly in developing countries. The paper concludes that the systematic review may be a very useful tool that can be used for evidence-based health system research to address specific policy issues; however, research on some health system/policy issues may not be appropriate to use the systematic review at all.