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In this paper, the parameters of a prototype runner of an axial flow pump are optimized by using the immersion boundary–lattice Boltzmann numerical method based on a large-eddy simulation (LES-IB-LBM). A fish-friendly axial flow pump with a leading-edge thickness of 11.4 mm and blade cutting angle of 18° is proposed. Through experiments, the living conditions of many kinds of fish in extremely positive and negative pressure environments are explored, and the probability of damage caused by pump to fish is analyzed by taking −40 kPa as the low-pressure damage threshold. The flow passage of the fish-friendly axial flow pump effectively guides the fish to low-risk areas, reducing the risk of friction, shear, and impact damage to the fish. The total impact mortality ratio of runners before and after the axial flow pump optimization is close to 7:1.