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ABSTRACT Background Fortification, the addition of essential micronutrients during food processing, reduces mortality and malnutrition. Our objective was to comprehensively synthesize global evidence on the cost-effectiveness (CE) and cost savings of food fortification. Methods We employed systematic review methodology, PROSPERO registration (CRD42023493795), searching six databases to January 2024. Eligible studies included economic analyses comparing staple food post-harvest micronutrient fortification to no fortification. Quality appraisal used Philips’ modeling framework. We converted incremental cost-effectiveness ratios (ICERs) to 2022 US$; and synthesized the data overall and by micronutrient. For illustration, findings were also categorized by “hypothetical” CE thresholds based on common example percentages of gross domestic product per capita (GDP pc) per country. Findings After screening 6,425 abstracts, 56 studies in 66 reports were included, reporting >200 analyses. Sixty-three countries were represented, including >40 low- and middle-income economies (LMICs). Most frequent interventions were: vitamin A, folic acid, iron, and iodine added to cereal grains/products (e.g., flours) and condiments (e.g., oils, sugar, salt). Models were heterogeneous and employed various perspectives. Most evaluations (58%; 135/232) had ICERs less than $150 per disability-adjusted life year (DALY) averted (or healthy life year gained). We found 87% (201/232) overall were within a hypothetical CE threshold of “50% GDP pc”. With an example “35% GDP pc” level among LMICs, 84% (190/227) were estimated to be cost-effective; and 71% (37/52) were less than “20% GDP pc” among low-income countries. Additionally, six out of eight cost-utility studies’ ICERs were dominant. Moreover, 47 total unique benefit–cost ratios found benefits outweighed costs, ranging from 1·50:1 to 100·6:1. Interpretation Food fortification programs are likely cost-effective in the majority of contexts. While cost-effectiveness evaluations are specific to local factors and methodology, this research can assist with evidence-informed decision-making for global health policy and priority setting, particularly in resource-constrained economies. Funding U.S. Agency for International Development. Research in context Evidence before this study Database searches of MEDLINE, Embase, EconLit, and the National Health Service Economic Evaluation Database (NHS EED), from inception to January 2024, were conducted for previous systematic reviews on the economics of food fortification. No language, date, or publication status limits were applied. While the impact of food fortification on health outcomes has been widely studied, we did not find a comprehensive systematic review of the cost-effectiveness of all types of large-scale food fortification. Several smaller systematic reviews and some in-depth narrative reviews have studied the economics of food fortification but their aims were not broad evaluations of its cost-effectiveness as they limited their scope to specific foods or nutrients. Added value of this study This large systematic review of 56 economic studies reporting over 200 analyses provides a substantially broader synthesis of the economic evidence base of food fortification. Of note, it also spans 63 countries, including >40 low- and middle-income economies (LMICs), thereby augmenting the international research on a system-level intervention for reducing global malnutrition, mortality, and morbidity. We found that food fortification programs are likely cost-effective in the majority of contexts. Overall, across the many diverse economic models, incremental cost-effectiveness ratios (ICERs) for most evaluations (58%; 135/232) were less than $150 per disability-adjusted life year (DALY) averted (or healthy life year gained). As an illustration using a “hypothetical” cost-effectiveness threshold example of ‘35% of gross domestic product (GDP) per capita’ among LMICs, 84% (190/227) of ICERs were estimated to be cost-effective. Additionally, six out of eight cost-utility studies’ (i.e., measuring quality-adjusted life years, QALYs) ICERs were dominant (i.e., fortification was less costly and more effective than the comparator). Moreover, 47 benefit–cost ratios found that food fortification programs’ benefits outweighed the costs (with ranges from 1·50:1 to 100·6:1). Implications of all the available evidence There are significant policy implications from this research. The decision by policymakers to enact or strengthen food fortification programs in their countries is predicated by many factors, including costs and cost-effectiveness. Synthesizing the evidence of the economic implications of food fortification could translate to improved global advocacy efforts by partners seeking to introduce and scale up food fortification programs. Nutrition for Growth aims to mobilize governments, bilateral agencies, private investors, businesses, civil society, donors, and others to increase and sustain their funding for nutrition actions, especially those that are evidence-based. Through the Global Nutrition Report, such financial commitments are being tracked internationally. The expectation is that this more robust evidence base of the cost-effectiveness of large-scale food fortification will encourage greater investment in initiating and strengthening fortification programs where they are needed. While cost-effectiveness evaluations are specific to local factors and methodology, this research can assist with evidence-informed decision-making for global health policy and priority setting, particularly in resource-constrained economies.