Ebselen (1), the quintessential mimic of the antioxidant selenoenzyme glutathione peroxidase (GPx), is a potential chemopreventative for various diseases associated with oxidative stress. Density-functional theory (DFT) and solvent-assisted proton exchange (SAPE) are used to model the complex mechanism for scavenging of reactive oxygen species by 1. SAPE is a microsolvation method designed to approximate the role of bulk solvent in chemical processes involving proton transfer. Consistent with experimental studies, SAPE studies predict the reaction of 1 with thiol (RSH) to form a selenenyl sulfide 2 to be preferred under most conditions, with an alternate pathway through a selenoxide 3 possible at high reactive oxygen species (ROS) concentrations ([ROS] >> [RSH]). The reduction of 2 to the selenol 4, known to be rate-determining in the protein, has a high SAPE activation barrier due to a strong Se center dot center dot center dot O interaction which reduces the electrophilicity of the sulfur center of the -SeS- bond of 2. Thiols, such as dithiols and peptide-based thiols, are expected to overcome this barrier through structural features that increase the probability of attack at this sulfur. Thus, in vivo, the GPx-like pathway is the most likely mechanism for 1 under most circumstances, except, perhaps, under extreme oxidative stress where initial oxidation to 3 could compete with formation of 2. Simple thiols, used in various in vitro studies, are predicted by SAPE modeling to proceed through oxidation of 2 to a seleninyl sulfide intermediate. Overall, SAPE modeling provides a realistic interpretation of the redox mechanism of 1 and holds promise for further exploration of complex aqueous-phase reaction mechanisms.