In this study, Chinese rare minnow (Gobiocypris rarus) larvae were exposed to the control group, Cd concentrations (0.5 and 2.5 mg/L), and Hg concentrations (0.1 and 0.3 mg/L) for 96 h. Transcriptome analysis showed that 816 and 1599 significantly differentially expressed genes (DEGs) were identified in response to 2.5 mg/L Cd²⁺ and 0.3 mg/L Hg²⁺, respectively. Functional enrichment analysis revealed that DEGs were mostly associated with immune responses after Cd exposure, such as antigen processing and presentation, phagosome, apoptosis, and lysosome. Similarly, functional enrichment analysis showed that many pathways were mostly involved in metabolism after Hg exposure, such as glutathione metabolism and starch and sucrose metabolism. Results of two-dimensional electrophoresis (2-DE) showed that the abundance of 10 protein spots was significantly altered in the Cd²⁺ treatments. The proteomic analysis demonstrated that Cd toxicity might impair cytoskeletal and cell motility-related protein activity in the liver of G. rarus. Similarly, the abundance of 24 protein spots was significantly altered in the Hg²⁺ treatments. Hg toxicity regulates the expression of proteins belonging to several functional categories, including cytoskeleton, oxidative stress, digestive system, and energy metabolism. This study provides valuable relevant insight into the molecular mechanisms in response to Cd or Hg toxicity in aquatic organisms and will help screen for potential biomarkers to respond to Cd and Hg pollutants.