Temperature is an important factor affecting the growth, development and survival of marine organisms. A short episode of high temperature has been proven to be a severe threat to sustainable shellfish culture. Zhikong scallop (Chlamys farreri), a shellfish with broad economic and biological value in North China, has frequently experienced heat stress in summer in recent years. To understand the effects of heat stress on shellfish, the metabolism of C. farreri was analyzed after exposure to 27 °C for either 6 h or 30 d. After 6 h of heat stress exposure, a total of 326 and 264 significantly different metabolites (SDMs) were identified in gill and mantle tissues, respectively. After 30 d of heat stress exposure, a total of 381 and 341 SDMs were found in the gill and mantle tissues, respectively. These SDMs were mainly related to the metabolism of amino acids, carbohydrates, lipids and nucleotides. A decline in pyruvic acid, and an increase in citric acid and fumaric acid in the gills and mantle of C. farreri indicated an alteration in energy metabolism, which may be attributed to increased ATP production in order to overcome the heat stress. Among the SDMs, 33 metabolites, including pyruvic acid, glycine and citric acid, were selected as potential biomarkers for heat stress response in C. farreri. In addition, a decline in glutamine and β-Alanine levels indicated oxidative stress in C. farreri exposed to heat, as well as an increase in the total antioxidant capacity (T-AOC). Our findings suggested C. farreri have the potential to adapt to heat stress by regulating energy metabolism and antioxidant capacity.