Barry Smith contributes to both theoretical and applied research in ontology. He has authored over 750 publications with over 50,000 citations and an h-index of 108. His research has been funded by the National Institutes of Health, the US, Swiss and Austrian National Science Foundations, the US Departments of Defense (DoD) and Homeland Security (DHS), the Humboldt and Volkswagen Foundations, and the European Union. He is Distinguished Julian Park Professor of Philosophy and Professor of Biomedical Informatics and of Computer Science in the University at Buffalo. He is also Director of the National Center for Ontological Research.

Smith is lead developer of Basic Formal Ontology (BFO), a top-level ontology used by over 700 ontology development groups across the world and recently documented as international standard ISO/IEC 21838-2. BFO is also part of the mandated ontology baseline of the Department of Defense and Office of the Director of National Intelligence and is a DOD Joint Enterprise Standards Committee (JESC) standard .

Smith's work led to the formation of the Open Biomedical Ontologies (OBO) Foundry, a set of widely used resources designed to support information-driven research in biology and biomedicine. He is one of the founders of the Industrial Ontologies Foundry (IOF) and he also contributes to the ontology work of the Department of Homeland Security, of the Department of Defense and Intelligence Community Ontology Working Group (DIOWG), and of the Five Eyes Ontology Working Group (FOWG).

Most recently Smith has co-authored with the German AI entrepreneur and mathematician Jobst Landgrebe a book entitledWhy Machines Will Never Rule the World, published by Routledge in 2023. An expanded second edition will appear in spring 2025.