Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in roughly five percent of the patients taking them. Studies attribute differences in toxicities to minor structural modifications to the diphenylamine scaffold rather than inherent toxicity of diphenylamine itself. We hypothesize that substituents of marketed diphenylamine NSAIDs determine the preference and efficiency of bioactivation pathways relative to overall drug clearance. We tested the hypothesis through a novel integration of bioinformatic, computational, and experimental approaches. Initially, we parsed the FDA DILIrank database containing liver toxicity information on marketed drugs and modeled their potential bioactivation into quinones to identify a family of seven clinically relevant diphenylamine NSAIDs including the well-studied diclofenac. These drugs fell into two subgroups, i.e. acetic acid and propionic acid diphenylamines, varying in hepatotoxicity risks and modeled bioactivation propensities. Next, we carried out novel steady-state kinetic studies to assess bioactivation pathways by trapping quinones with dansyl glutathione. Analysis of the glutathione adducts by MS characterized structures while dansyl fluorescence provided quantitative yields for their formation over time. The resulting kinetics identified four possible bioactivation pathways among the drugs, but the preference and efficiency of reactions depended upon structural modifications to the diphenylamine scaffold. Strikingly, diphenylamine dihalogenation promotes the formation of quinone metabolites through four distinct metabolic pathways with high efficiency, whereas those without aromatic halogen atoms were metabolized less efficiently through two or fewer metabolic pathways. Despite differences in bioactivation, overall metabolism of the drugs was comparable with bioactivation accounting for 4 to 13% of clearance. Lastly, we calculated daily bioload exposure from the quinone metabolites based on bioactivation efficiency, drug bioavailability, and maximal daily dose. The results revealed stratification into the two diphenylamine subgroups; propionic acid diphenylamines had a nearly four-fold greater daily bioload on average compared to acetic acid diphenylamines. However, the lack of sufficient study on the corresponding liver toxicities for all drugs prevented a more correlative analysis. Future work will identify responsible enzymes to understand the role of these structural modifications in metabolic clearance and bioactivation and subsequent drug-induced liver injury. These findings will provide critical insights on the impact of diphenylamine bioactivation as a precursor to DILI and thus, provide a foundation for better risk assessment in drug discovery and development.