BACKGROUND: Each year almost 3 million newborns die within the first 28 days of life, 2.6 million babies are stillborn, and 287,000 women die from complications of pregnancy and childbirth worldwide. Effective and cost-effective interventions and behaviours for mothers and newborns exist, but their coverage remains inadequate in low- and middle-income countries, where the vast majority of deaths occur. Cost-effective strategies are needed to increase the coverage of life-saving maternal and newborn interventions and behaviours in resource-constrained settings. METHODS: A systematic review was undertaken on the cost-effectiveness of strategies to improve the demand and supply of maternal and newborn health care in low-income and lower-middle-income countries. Peer-reviewed and grey literature published since 1990 was searched using bibliographic databases, websites of selected organizations, and reference lists of relevant studies and reviews. Publications were eligible for inclusion if they report on a behavioural or health systems strategy that sought to improve the utilization or provision of care during pregnancy, childbirth or the neonatal period; report on its cost-effectiveness; and were set in one or more low-income or lower-middle-income countries. The quality of the publications was assessed using the Consolidated Health Economic Evaluation Reporting Standards statement. Incremental cost per life-year saved and per disability-adjusted life-year averted were compared to gross domestic product per capita. RESULTS: Forty-eight publications were identified, which reported on 43 separate studies. Sixteen were judged to be of high quality. Common themes were identified and the strategies were presented in relation to the continuum of care and the level of the health system. There was reasonably strong evidence for the cost-effectiveness of the use of women's groups, home-based newborn care using community health workers and traditional birth attendants, adding services to routine antenatal care, a facility-based quality improvement initiative to enhance compliance with care standards, and the promotion of breastfeeding in maternity hospitals. Other strategies reported cost-effectiveness measures that had limited comparability. CONCLUSION: Demand and supply-side strategies to improve maternal and newborn health care can be cost-effective, though the evidence is limited by the paucity of high quality studies and the use of disparate cost-effectiveness measures. TRIAL REGISTRATION: PROSPERO_ CRD42012003255.