Flavor chemicals contribute to the appeal and toxicity of tobacco products, including electronic nicotine delivery systems (ENDS). The assortment of flavor chemicals available for use in tobacco products is extensive. In this study, a chemistry-driven computational approach was used to evaluate flavor chemicals based on intrinsic hazardous structures and reactivity of chemicals. A large library of 3012 unique flavor chemicals was compiled from publicly available information. Next, information was computed and collated based on their (1) physicochemical properties, (2) global harmonization system (GHS) health hazard classification, (3) structural alerts linked to the chemical's reactivity, instability, or toxicity, and (4) common substructure shared with FDA's harmful and potentially harmful constituents (HPHCs) flavor chemicals that are respiratory toxicants. Computational analysis of the constructed flavor library flagged 638 chemicals with GHS classified respiratory health hazards, 1079 chemicals with at least one structural alert, and 2297 chemicals with substructural similarity to FDA's established and proposed list of HPHCs. A subsequent analysis was performed on a subset of 173 chemicals in the flavor library that are respiratory health hazards, contain structural alerts as well as flavor HPHC substructures. Four general toxicophore structures with an increased potential for respiratory toxicity were then identified. In summary, computational methods are efficient tools for hazard identification and understanding structure-toxicity relationship. With appropriate context of use and interpretation, in silico methods may provide scientific evidence to support toxicological evaluations of chemicals in or emitted from tobacco products.