The Yesso scallop Patinopecten yessoensis is one of the most important aquaculture species in Asian countries because of its high economic value, but it has suffered severe infection by Polydora in recent years, causing great economic losses. Polydora mainly parasitizes the left valves of the Yesso scallop, especially the region around the adductor muscle, badly damaging the shell structure and making the shell particularly fragile. To investigate the response mechanism of the Yesso scallop to Polydora, a histological study was performed on healthy and diseased Yesso scallop mantle tissues, which are thought to be responsible for shell formation. In the present study, separate histological and histochemical changes in different mantle regions were detected for the first time. In the diseased scallops, abundant mucous cells containing acid mucopolysaccharides were found in the epidermis of the outer fold, along with a great increase in cilia on the inner epidermis, and a significant increase in mucous cells secreting acid mucopolysaccharides was observed in the middle fold and the central mantle, suggesting an accelerated process of secretion and transportation of shell substances. These changes in the different mantle regions were probably responsible for the repair of different shell layers. The present study provides valuable information for the function of mantle tissue in shell formation and is helpful for genetic breeding of disease-resistant scallops in the future.