Interactive effects of ocean acidification and ocean warming on marine calcifiers vary among species, but little is known about the underlying mechanisms. The present study investigated the combined effects of seawater acidification and elevated temperature (ambient condition: pH 8.1 × 23 °C, stress conditions: pH 7.8 × 23 °C, pH 8.1 × 28 °C, and pH 7.8 × 28 °C, exposure time: two months) on the transcriptome and biomineralization of the pearl oyster Pinctada fucata, which is an important marine calcifier. Transcriptome analyses indicated that P. fucata implemented a compensatory acid-base mechanism, metabolic depression and positive physiological responses to mitigate the effects of seawater acidification alone. These responses were energy-expensive processes, leading to decreases in the net calcification rate, shell surface calcium and carbon content, and changes in the shell ultrastructure. Elevated temperature (28 °C) within the thermal window of P. fucata did not induce significant enrichment of the sequenced genes and conversely facilitated calcification, which was detected to alleviate the negative effects of seawater acidification on biomineralization and the shell ultrastructure. Overall, this study will help elucidate the mechanisms by which pearl oysters respond to changing seawater conditions and predict the effects of global climate change on pearl aquaculture.