The salmon louse (Lepeophtheirus salmonis) is an ectoparasite feeding on mucus, skin, and blood of salmonids. On parasitised fish erosions and, at later lice stages, ulcerations appear at the louse feeding site. In susceptible species like Atlantic salmon (Salmo salar) with a limited rejection of lice, only a mild inflammatory response with minor influx of immune cells is seen at these lesions, as the salmon louse secrete proteins that can dampen immune responses. In a previous study, Lepeophtheirus salmonis labial gland protein 3 (LsLGP3) was suggested to dampen cellular responses, and the present study aimed at increasing our understanding of its mode of action. LsLGP3 was found to be secreted on to the host skin, and both in vivo and in vitro experiments were performed to elucidate its function. Histological analysis of the louse attachment site revealed an epidermal and dermal influx of mainly macrophages and granulocytes after 5 days post infestation. The immune cell influx was deeper in the dermis throughout the louse infestation, and LsLGP3 may be involved in dampening this response. Enriched populations of Atlantic salmon B-cells, T-cells, granulocytes, and monocytes were exposed to recombinant LsLGP3 (recLGP3) in vitro, resulting in a significant decrease in cell viability compared to non-exposed controls. An apoptotic cell morphology with "beads-on-a-string" like protrusions was seen in all leukocyte cell fractions after recLGP3 exposure, but not in erythrocytes or keratocytes. A decreased viability was also detected in pink salmon leucocytes, which was not in leucocytes from non-salmonid species. These functional insights suggest that LsLGP3 specifically induces apoptosis of salmonid leukocytes and is likely a key protein secreted by the lice that disables the Atlantic salmon ability to mount an adequate immune response towards the salmon louse. In vivo LsLGP3 knock down studies indicated that the effect is localised primarily at the lice feeding site, without affecting immune cells that are not situated adjacent to the lice-inflicted lesion. The findings from this study could significantly aid in the development of new immune based anti-salmon louse prophylactic measures and treatments.