Background Social determinants of health (SDoH) have been described by the World Health Organization as the conditions in which individuals are born, live, work, and age. These conditions can be grouped into 3 interrelated levels known as macrolevel (societal), mesolevel (community), and microlevel (individual) determinants. The scope of SDoH expands beyond the biomedical level, and there remains a need to connect other areas such as economics, public policy, and social factors. Objective Providing a computable artifact that can link health data to concepts involving the different levels of determinants may improve our understanding of the impact SDoH have on human populations. Modeling SDoH may help to reduce existing gaps in the literature through explicit links between the determinants and biological factors. This in turn can allow researchers and clinicians to make better sense of data and discover new knowledge through the use of semantic links. Methods An experimental ontology was developed to represent knowledge of the social and economic characteristics of SDoH. Information from 27 literature sources was analyzed to gather concepts and encoded using Web Ontology Language, version 2 (OWL2) and Protégé. Four evaluators independently reviewed the ontology axioms using natural language translation. The analyses from the evaluations and selected terminologies from the Basic Formal Ontology were used to create a revised ontology with a broad spectrum of knowledge concepts ranging from the macrolevel to the microlevel determinants. Results The literature search identified several topics of discussion for each determinant level. Publications for the macrolevel determinants centered around health policy, income inequality, welfare, and the environment. Articles relating to the mesolevel determinants discussed work, work conditions, psychosocial factors, socioeconomic position, outcomes, food, poverty, housing, and crime. Finally, sources found for the microlevel determinants examined gender, ethnicity, race, and behavior. Concepts were gathered from the literature and used to produce an ontology consisting of 383 classes, 109 object properties, and 748 logical axioms. A reasoning test revealed no inconsistent axioms. Conclusions This ontology models heterogeneous social and economic concepts to represent aspects of SDoH. The scope of SDoH is expansive, and although the ontology is broad, it is still in its early stages. To our current understanding, this ontology represents the first attempt to concentrate on knowledge concepts that are currently not covered by existing ontologies. Future direction will include further expanding the ontology to link with other biomedical ontologies, including alignment for granular semantics.