The mucosa is the first line of defense in aquatic organisms, were epidermal cell, mucus, glycoproteins, antimicrobial molecules, microorganism and metabolites converge to shape the structure and functioning of the mucosal environment. While multiple studies have shown protective proprieties of the mucosa in marine organisms to bacterial and viral infections, its role in the resistance of fish against ectoparasite remains less understood. Ectoparasite, like the sea lice (Caligus rogercresseyi), have become one of the most challenging issues for salmon aquaculture worldwide. Although delousing drugs are currently used to control the parasite, these treatments threat the sustainable development of salmon aquaculture. Thus, understanding the importance of the mucosa in salmon resistance to sea lice could lead to the development of novel tools and strategies to manage this disease. To evaluate this, a metagenomic and metabolomic approach was used to identify differences in the microbial communities and metabolites in the skin and gut mucosa of Atlantic salmons with contrasting resistance to sea lice. The results evidenced that the most significant changes in the mucosa between resistant and susceptible individuals were found in the skin, and in lesser extent in gut. While no significant differences were found in the microbial diversity of gut mucosa, the alpha diversity of the skin mucosa was significantly higher (p < 0.05) in resistant salmonids compared with susceptible ones (Fig. 1A). A Linear discriminant analysis Effect Size (LEfSe) analysis evidenced that the skin mucosa of susceptible individuals were significantly associated with bacteria from the Comamonas and Vibrio genus, while the resistant phenotype was significantly associate with bacteria from the Pseudomonas, Novosphingobium and Labrys genus (Fig 1B). Regarding metabolome analysis, a t-test was used to identify metabolites with significant differences in gut and skin mucosa from resistant and susceptible salmons. The results evidenced a higher number of metabolites with differential abundance (FC > 4 and p < 0.01) in the skin that in the gut mucosa. Differences were also found in the distribution of this metabolites between resistant and susceptible salmonids. While the largest number of differentially abundant metabolites in gut mucosa were associated with susceptible individuals, the skin mucosa evidence a higher number of metabolites significantly associated with the resistant individuals (Fig. 1C). Overall, our results provide evidence about the differences in the metagenomic and metabolomic profiles between Atlantic salmon with contrasting resistance to sea lice infestation. These results open new perspectives about the role of the mucosal environment in the resistance of salmonids to sea lice that could be further explore for the development of novel and sustainable strategies to deal with sea lice infestation in salmon aquaculture.