The purpose of this study was to characterize histopathological changes induced by the sea louse Caligus rogercresseyi in juvenile individuals of rainbow trout (Oncorhynchus mykiss). Specific effects were determined for mucus-secreting cells, mast cells/eosinophilic granule cells (MCs/EGCs) and activation of pro-inflammatory caspase-1, which are involved in the inflammatory response. As expected, C. rogercresseyi eroded the skin to varying degrees, with increased mucus-secreting cells in the epidermis and melanophores in the dermis. Gill responses included epithelial hyperplasia, secondary lamellae fusion, an increased quantity of mucus-secreting cells in the epithelium, and MCs/EGCs in the connective tissue. Other histological changes included abundant MCs/EGCs and secretory cells in the intestine, as well as numerous melano-macrophage centres in head kidney stroma cells. Finally, the observed inflammatory response was associated with active caspase-1 detection in the gills, but not in the other assessed organs. In conclusion, C. rogercresseyi induced significant histopathological alterations in O. mykiss skin and gills and minor histological changes in the intestine and head kidney, which may reflect the overall inflammatory response of rainbow trout to infestation with sea lice.