The fan mussel Pinna nobilis is currently on the brink of extinction due to a multifactorial disease mainly caused to the highly pathogenic parasite Haplosporidium pinnae, meaning that the selection pressure outweighs the adaptive potential of the species. Hopefully, rare specimens have been observed somehow resistant to the parasite, stretching the need to identify the traits underlying this better fitness. Among the candidate to explore at first intention are fast-evolving immune genes, of which toll-like receptor (TLR). In this study, we examined the genetic diversity at 14 TLR loci across Pinna nobilis, Pinna rudis and Pinna nobilis x Pinna rudis hybrid genomes, collected at four physically distant regions, that were found to be either resistant or sensitive to the parasite H. pinnae. We report a high genetic diversity, mainly observed at cell surface TLRs compared to that of endosomal TLRs. However, the endosomal TLR-7 exhibited unexpected level of diversity and haplotype phylogeny. The lack of population structure, associated with a high genetic diversity and elevated dN/dS ratio, was interpreted as balancing selection, though both directional and purifying selection were detected. Interestingly, roughly 40% of the P. nobilis identified as resistant to H. pinnae were introgressed with P. rudis TLR. Specifically, all these P. nobilis carried a TLR-7 of P. rudis origin. On the contrary, sensitive P. nobilis were not introgressed, at least at TLR loci, highlighting that TLR-7 might be a potent effector of resistance. Small contributions of TLR-6 and TLR-4 single nucleotide polymorphism to the cluster of resistant and sensitive groups could be detected, but their specific role in the resistance remains highly speculative. This study brings additional knowledge on the molecular processes of resistance to H. pinnae and will likely contribute to the conservation efforts carried out to prevent from extinction this Mediterranean endemic species.