Thermal stress in marine environments is likely to become more widespread in marine environments. Understanding age-related physiological adaptations to thermal stress is critically important for predicting the impacts of global climate change on marine biodiversity. The typical burrowing bivalve, Manila clam Ruditapes philippinarum, was selected to explore molecular and physiological responses to thermal stress and how the effects varied with ages (juvenile VS. adults). When the temperature increased to 30.6 °C, the significantly higher rates of burrowing behavior was found in juvenile clams than that of adult clams (60 % VS. 26.7 %). As the thermal stress increased to 44.6 °C, the survival rate was found to be 49.7 % in juvenile clams, compared to 100 % mortality in adult clams. According to the comparative transcriptomics, the significant up-regulation of genes related to neuropeptide and extracellular matrix (ECM) were potentially involved in active muscle contractility and wound healing ability in juveniles. This may be responsible for their high rates of burrowing behavior in response to the thermal stress. In contrast to juveniles, multiple down-regulated genes involved in antioxidant and energy metabolism were detected in adults, which may be associated with disruption of their energy homeostasis, cell damage and dysfunction, resulting in less capability of adult clams to resist the thermal conditions. The present study will provide new evidences on age differences of clams in response to thermal stress, suggesting clam age or body size constrains their thermal tolerance. These findings will not only shed lights on the molecular mechanism of clams with different ages or sizes in response to thermal stress, but also provide insights into the prediction of future biodiversity and sustainable aquaculture production in a warming world.