Increased agricultural production will be necessary to feed rapidly growing populations in sub-Saharan Africa, where many households currently practice low-input, subsistence farming. Efforts to expand food production will likely include agricultural intensification to enhance productivity of existing cropland, and holistic frameworks are needed to quantitatively evaluate trade-offs and synergies between intensification and other dimensions of development. Beyond well-documented interactions with environmental and economic issues, intensification’s complex relationship with human health should take a position of primary importance in any framework designed to advance food security. While intensification can lead to improvements in nutritional status, neglecting sources of potential adverse health impacts, including water source contamination and direct contact with agricultural inputs or environmental pathogens, may undermine prospective gains. Harmonizing goals will require interdisciplinary teams applying frameworks that integrate tools such as quantitative risk assessment, environmental life cycle assessment, and economic models to comprehensively evaluate potentially dissimilar strategies across common metrics while accounting for interdependencies and uncertainties. With local implementation partners, these teams will be well-equipped to develop holistic interventions that effectively promote food security and protect human health while considering local constraints and opportunities across multiple dimensions of development.