The mollusс–trematode system exemplifies a parasitic relationship with a very long evolutionary history and has significantly altered the functions of both organisms. The influence of trematode parasites on mollusсs is complex and multifaceted: it may include immune suppression, alterations in energy metabolism, gigantism, parasitic castration, shell deformation, changes in behavior and motility, etc. Nevertheless, the molecular basis of host-parasite interactions between snails and flukes is still underinvestigated, and thorough studies of trematode-caused changes in the host at the molecular level are of high demand in parasitology. In this study, we analyzed changes in gene expression in tissues of Littorina saxatilis snails infected with Microphallus piriformes trematodes. Our comparative transcriptomic analysis of infected vs healthy molluscs revealed significant changes in expression of 160 genes associated with biomolecule catabolism, morphogenesis and tissue remodeling, immune system function, etc. The observed changes in expression of genes associated with lipid and protein metabolism are likely to be associated with parasitic exploitation of the host’s energy resources, while tissue remodeling processes may be attributed to homeostasis maintenance in the infected host. Additionally, we performed a targeted search and identified homologues of a number of immune-related genes: toll-like receptors, peptidoglycan recognition proteins, etc. In the context of immune response-related genes, there was a noticeable decrease in the expression of genes associated with the production of reactive oxygen species and reactive nitrogen species in the infected snails, specifically the dual oxidase and nitric oxide synthase genes. Our data suggests a fundamental modification of the host’s metabolism induced by the parasite and add to the previous studies on the interaction between the Littorina molluscs and the Microphallus trematodes.