This article demonstrates how a decision-making framework for health system and public health decisions can be applied to national food fortification programs. Background Although the potential impact of food fortification to improve the micronutrient status of populations has been demonstrated beyond a doubt, it is constrained in practice by critical gaps in program design and implementation. These are partly linked to suboptimal decision making. Objectives We aimed to demonstrate how the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence to Decision (EtD) framework for health system and public health decisions can be applied to formulate recommendations and make decisions in national food fortification programming. Methods Following a program impact pathway, we reviewed the literature to define the key decision types and identify the corresponding decision makers necessary for designing and implementing effective food fortification programs. We then applied the GRADE EtD framework to the Nigerian fortification program to illustrate how evidence-informed assessments and conclusions can be made. Results Fortification program decisions were classified into 5 types: 1) program initiation; 2) program design; 3) program delivery; 4) program impact; and 5) program continuation. Policymakers, food processors, and (in cases dependent on or considering external funding) development partners are the main decision makers in a fortification program, whereas technical partners play important roles in translating evidence into contextualized recommendations. The availability and certainty of evidence for fortification programs are often low (e.g., quality and coverage data are not routinely collected and there are challenges evaluating impact in such population-based programs using randomized controlled trials) yet decisions must still be made, underscoring the importance of using available evidence. Furthermore, when making program initiation and continuation decisions, coordination with overlapping micronutrient interventions is needed where they coexist. Conclusions This framework is a practical tool to strengthen decision-making processes in fortification programs. Using evidence in a systematic and transparent way for decision making can improve fortification program design, delivery, and ultimately health impacts.