Clostridium butyricum (CB) has received much attention as a probiotic; however, few studies have focused on its effects on liver health. Here, we studied the influence of CB on the liver health of spotted sea bass through transcriptomic and metabolomic studies and preliminarily explored its molecular mechanisms. This study showed that CB significantly reduced hepatic aspartate aminotransferase (AST) activity and increased alkaline phosphatase (AKP) and acid phosphatase (ACP) activity (P < 0.05). CB has demonstrated significant effects in strengthening liver immunity and can increase hepatic amylase and trypsin activities and promote hepatic catabolism of carbohydrates and amino acids. Integration of the liver Transcriptomics and metabolomics showed altered transcript levels of mainly gluconeogenic, lipogenic, and amino acid metabolic pathways. It regulated the abundance of metabolic biomarkers such as arachidonate, crotonyl-CoA, and D-glucose 1-phosphate. Our findings support that CB can reduce liver damage in spotted sea bass, enhance liver immunity, and improve liver metabolism.