Food is the main source of energy for animals, and food abundance affects animal bioenergetics in terms of how energy is allocated among growth, maturation, and reproduction. However, food resources are sometimes insufficient for mussel because of weather conditions, specific periods of their reproductive cycles and food restriction. Marine mussels are one of the most important marine genera globally and are widely distributed in estuarine and marine environments, as well as in the subtidal and intertidal zones, and are commercially important. In order to explore the physiological and biochemical responses and molecular adaptation mechanism of mussels under starvation stress, the survival rate statistics, energy metabolism related enzyme activity determination and gonad transcriptome sequencing and analysis were carried out on two-year Mytilus coruscus under normal feeding (control group) and starvation treatment (starvation group). The results showed that the survival rate of M. coruscus reached 86% after 90 days of starvation. Under starvation stress, the activities of phosphoenolpyruvate carboxykinase (PEPCK) were significantly increased, but the activities of hexokinase (HK), phosphofructokinase (PFK), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) were significantly decreased (P<0.05). By Illumina Hiseq X10 high-throughput sequencing platform, 31 596 762 and 26 810 506 effective data with unique annotation on the genome of the control group and the starvation group were obtained, and 4 130 differentially expressed genes were screened. There were 2 082 up-regulated and 2 048 down-regulated genes. GO functional analysis showed that differential genes were mainly enriched in metabolic process, organelle tissue and enzyme activity. KEGG enrichment analysis showed that differential genes were significantly enriched in metabolic pathways related to cell division, such as DNA replication, mismatch repair and base excision repair. The results of this experiment showed that mussels could maintain their survival under starvation stress by reducing energy metabolism and slowing down cell division. This study preliminarily reveals the physiological and biochemical responses and molecular regulation mechanism of M. coruscus under starvation stress, which provides important theoretical basis for further analysis of the molecular strategies of mussels in response to starvation stress, and also provides new ideas for revealing their energy utilization and redistribution and physiological countermeasures to adapt to starvation stress.