Ocean acidification (OA) severely affects marine bivalves, especially their calcification processes. However, very little is known about the fate of symbiont-bearing giant clams in an acidifying ocean, hampering our ability to develop strategies for conservation of this ecologically and economically important group in coral reef ecosystems. Here, we explored integrated responses of the fluted giant clam Tridacna squamosa to reduced seawater pH (~7.6) at different levels of biological organization. Seawater acidification did not elicit significant decreases in survival and shell growth performance, indicating the tolerance of T. squamosa under moderately acidified conditions. Yet, significantly reduced net calcification rate demonstrated the calcifying physiology sensitivity to OA, in line with significantly declines in symbiont photosynthetic yield and zooxanthellae density which in turn lowered the amount of energy supply for energetically expensive calcification processes. Subsequent transcriptome sequencing and comparative analysis of differentially expressed genes revealed regulation of calcification processes, such as transport of calcification substrates, acid-base regulation, synthesis of organic matrix in the calcifying fluid, as well as metabolic depression in response to OA. Taken together, the integration of organismal, physiological, and molecular responses can provide a comprehensive understanding of how giants clams may respond to OA and make an important leap forward in predicting their fate in a rapidly acidifying ocean.