Crossbreeding is an effective approach to manage the genetic decline in aquaculture. One-way hybrids of Crassostrea sikamea (♀) and Crassostrea gigas (♂) have advantages in growth traits and adaptation to high temperature. Here, we used high- throughput sequencing to analyze the molecular processes in the hybrids under and after thermal stress. The hybrids were cultured in the seawater with an increasing temperature from 25℃ to 40℃ during 10 hours, which is regarded as the thermal stress stage. Then the temperature decreased from 40℃ to 25℃ within 2 h, which is regarded as the recovery stage. In this study, 1293 significant diffe- rentially expressed genes (DEGs) were obtained under thermal stress, of which 576 were upregulated and 717 were downregulated, and 740 significant differentially expressed genes (DEGs) were obtained in the recovery stage, of which the number of upregulated and downregulated genes was 409 and 331, respectively. The antigen processing and presentation, NOD-like, and NF-kappa B path- ways were significantly enriched during the thermal stress stage. The MAPK and PPAR signaling pathways were significantly enrich- ed during the recovery stage. The HSP70, HSP90, and CANX genes were strongly and rapidly upregulated in the control/thermal stress groups but were slightly less upregulated in the thermal stress/recovery group. These results indicate that the innate immune system or nonspecific immunity was deployed to protect interior tissues from thermal stress. In addition, 85％ of the mutual DEGs were involved in bidirectional regulation (up/down or down/up) when the oysters were removed from the thermal stress to recover. This study provides preliminary insight into the molecular response of C. sikamea (♀) and C. gigas (♂) hybrids to thermal stress and provides a basis for future studies on temperature-adaptation and the possible expansion of hybrid breeding.