Eugenol is a natural alkenylbenzene compound used in a variety of consumer products. There is limited evidence for the carcinogenicity of eugenol to experimental animals. However, in vitro tests for the genotoxic potential of eugenol have on occasion reported a positive result. In contrast, the structurally related alkenylbenzene methyleugenol is consistently reported as genotoxic and carcinogenic in vitro and in vivo. Metabolism of eugenol and methyleugenol has been documented but comparative kinetics have never been conducted in multiple species. Thus, we decided to investigate the bioactivation and detoxification kinetics of eugenol and methyleugenol in human, rat, and mouse to further assess their differential toxicity. The formation of a 1'-hydroxy proximate carcinogen, and a cytotoxic quinone methide, two key toxic metabolites for alkenylbenzenes, were quantified in hepatic and pulmonary microsomes and S9 fractions. Kinetic constants (app)Km, (app)Vmax, and CLint were measured for these reactions. We report that methyleugenol generates a significant amount of the 1'-hydroxy proximate carcinogen while eugenol glucuronidation prevents the formation of both 1'-hydroxyeugenol and the quinone methide. Comparative kinetics highlighted key metabolic differences between human, mouse, and rat, providing a mechanistic insight into the bioactivation and detoxification of alkenylbenzenes in each species.