Freshwater mussels are among the most endangered animal groups, highly sensitive to climate change due to their strict dependence on freshwater habitats. While freshwater mussels are often considered ecologically strict, their distribution across broad environmental gradients raises the possibility of population-specific adaptations mediated by phenotypic plasticity. This study investigates whether geographically and climatically distinct populations of two freshwater mussel species (Unio pictorum and Unio delphinus) exhibit different transcriptomic responses to prolonged heat stress and whether these responses reveal signs of local adaptation. We exposed northern and southern populations of both species to gradually increasing temperatures in controlled laboratory conditions, simulating a prolonged thermal extreme event, and RNA-seq was used to quantify differential gene expression. Results showed strong differences between northern and southern populations of the two species, both in the magnitude and functional composition of transcriptomic responses. Southern populations exhibited intense expression shifts involving classical stress pathways, heat shock proteins, detoxification (cytochrome P450s), apoptosis, and energy metabolism, while northern populations, particularly U. delphinus, showed a markedly subdued response. Notably, U. pictorum's northern population relied heavily on the cytochrome P450 family even at moderate temperatures, while the southern populations of both species activated broader proteostasis and immune responses at higher stress thresholds. These findings demonstrate clear population-specific phenotypic plasticity, shaped by environmental conditions rather than phylogenetic proximity. They underscore the need for conservation strategies to move beyond species-level management, embracing intraspecific variation as a buffer against climate impacts. As climate change accelerates, safeguarding the evolutionary potential encoded within populations, not just species, is essential to preserving biodiversity resilience.