To investigate the effects of predation of the paddle crab Charybdis japonica on the culture and survival of scallops (Mizuhopecten yessoensis) during bottom culture, we investigated the behavioral characteristics of three sizes (small, medium, and large) of scallops in response to exposure to crabs. We also measured the activities of superoxide dismutase, catalase, arginine kinase, and octopine dehydrogenase in the gill, adductor muscle, and mantle of scallops before and after exposure to predation. Tissues that showed significant differences between control and test specimens were selected for deep sequencing of the transcriptome to identify and validate the key genes that were sensitive to predation. We found that scallops escaped from crab predation by continuous shell closure or movement. Shell closure force increased with scallop size, and scallops of the same size that were stimulated by the presence of crabs closed their shell more frequently than control scallops. The shell closure ability of scallops of all sizes decreased with increasing duration of the experiment. The enzyme activities of the three scallop tissues changed significantly after continuous stimulation, and the trend was particularly obvious in the enzyme activities of the adductor muscles of the medium-sized scallops. Transcriptome analysis of the adductor muscles of medium-sized scallops revealed 780 differentially expressed genes (322 up-regulated and 458 down-regulated), and expression levels of C1ql4, CHRNA2, KIF13B, HMCN1, and PROM1A changed after stimulation by crabs. Their sequencing results were verified by quantitative real-time PCR. We hypothesize that these genes may be related to muscle movement and regulation in M. yessoensis after stimulation. In conclusion, when M. yessoensis is stimulated by the presence of predators, its behavioral characteristics and related physiological and ecological indexes undergo significant changes. The results are relevant for developing specifications for M. yessoensis seedling casting during bottom culture.