There is increasing attention to the use of Antarctic toothfish (Dissostichus mawsoni) and Patagonian toothfish (Dissostichus eleginoides). Understanding the responses of toothfish and other species to fishing activities favors the sustainable use of natural resources. We developed an end-to-end model OSMOSE-CooperationSea to simulate the food web dynamics in the Cooperation Sea and evaluate the impact of toothfish fishery. Fishes and cephalopods played important roles in the energy pathways from krill species and other zooplankton species to toothfish and Weddell seal (Leptonychotes weddellii) whose trophic levels were higher than 5.0. Adélie penguin (Pygoscelis adéliae), Crabeater seal (Lobodon carcinophaga), and Baleen whales were strongly krill-reliant. The spawning stock of toothfish decreased more quickly than the recruitments with increasing fishing pressure. Fishing impacts on the recruitments of toothfish were hysteretic due to the fishing selectivity. The model considered an ontogenetic diet shift of toothfish that mesopelagic fish was influential to toothfish juveniles. The overexploitation of toothfish stock might result in a trophic cascade that mesopelagic fish biomass increased and krill biomass declined. Adélie penguin, Crabeater seal, and Baleen whales preyed on more small fishes in response to the decline of krill biomass. Considering the impacts of changes in Antarctic krill availability, the biomass of Adélie penguin, Crabeater seal, and Baleen whales declined with a heavy toothfish fishery. The study highlights the importance of precautionary and ecosystem-based management to toothfish fishery.