Health systems strengthening (HSS) interventions are increasingly being implemented to improve maternal and child health (MCH) services in low- and middle-income countries (LMICs). This study reviews global literature on cost-effectiveness of HSS interventions in improving MCH. A systematic review was conducted. Keywords, based on World Health Organization framework on health systems and prior studies, were applied to search in bibliographic databases and on the web. Articles that estimated cost-effectiveness of HSS interventions in LMICs were included in the analysis. Each of the 24 selected studies from 15 countries was assessed in terms of quality and biases using Cochrane’s criteria. Review Manager and an Excel template were used to extract data and synthesize findings. HSS interventions concentrated on the components of service delivery, health financing, human resources and quality improvement. Within each component, there existed diverse strategies to strengthen health systems. Among the 24 studies, 15 were rated as high quality, 5 as medium and 4 as low quality. A majority of studies reported cost per disability-adjusted life year (DALY) averted or cost per quality-adjusted life year (QALY) gained; other studies reported cost per life saved or life year gained. However, studies used mixed perspectives of analyses. Compared with gross domestic product per capita, interventions in studies reporting cost per DALY averted or QALY gained were all cost-effective, including performance-based financing, health insurance and quality improvement. This review shows the diversity of HSS interventions in improving MCH, and their potential cost-effectiveness. However, the different perspectives employed in the studies, costing components included in the analyses, and heterogeneous measures of effectiveness and outputs, made it challenging to compare cost-effectiveness across all studies, calling for more and standardized cost-effectiveness studies. For policy making, it is critical to examine long-term cost-effectiveness of programs and cost-effectiveness of synergistic demand- and supply-side interventions.