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The replacement of fishmeal (FM) with economical and nutritious FM alternatives including plant and animal-based protein ingredients has become a global research priority. However, the presence of several anti-nutritional factors (ANFs) in these alternatives may impair nutrient utilization in fish. The supplementation of exogenous protease as feed additives could be an effective approach to improve the nutrient digestibility of these alternative proteins. Proteases are protein-digesting enzymes that catalyze the hydrolysis of complex protein macromolecules into simpler amino acids. Exogenous protease supplementation stimulates the activities of endogenous proteolytic enzymes for better nutrient digestion and absorption in fish. This review article summarizes the optimum protease supplementation levels in various fish species and its beneficial effects on growth performance, nutrient digestibility, intestinal morphology, digestive enzyme activities, whole-body composition, physiochemical parameters, immunity, and gene expression of fish. Moreover, the interactive effects of exogenous protease with organic acids and probiotics are also discussed. Overall, the supplementation of exogenous protease in fish feed is a viable solution for poor nutrient utilization of FM alternatives. Important gaps, however, exist in the current knowledge, particularly with regard to the effect of protease supplementation in animal-based proteins as most of the studies have focused on the effect of protease supplementation on plant-based proteins as FM alternatives. Moreover, additional studies focused on the effect of protease supplementation on the digestive enzyme activities, immunity, gut microbes and antioxidant parameters of fish will provide the basis for a better understanding of the mode of action of protease. The scarce knowledge in these areas limits the scope of protease supplementation as a feed additive in the aquaculture sector.