Dietary intake of a large amount of soybean meal (SBM) adversely affects the physiological condition and growth of fish, while SBM is a commonly used substitute for fish meal (FM) in aquaculture feed. In the present study, we investigated the effects of feeding an SBM-based diet (SBMD) for 8 weeks on hepatopancreatic metabolic condition in red seabream Pagrus major, using comprehensive analyses of the transcriptome and metabolome. Compared with fish fed an FM-based control diet (FMD), fish fed the SBMD showed delayed growth, decreases in hepatopancreatic somatic index and serum cholesterol concentration, and hepatopancreatic tissue degeneration. Transcriptome sequencing analysis identified 454, 353, and 566 differentially expressed genes at 2, 4, and 8 weeks, respectively. Analysis of the hepatopancreas metabolome using capillary electrophoresis-time-of-flight mass spectrometry identified 301 quantifiable metabolites in the FMD and SBMD groups. Transcriptome analysis showed increases in gene expression levels in the terpenoid and steroid biosynthesis pathways, suggesting that hepatic cholesterol biosynthesis was up-regulated in the SBMD group. In addition, the results of transcriptome and metabolome analyses suggested that the SBMD affects glutathione and glycine metabolism. These findings provide valuable information that enhances our understanding of the effects of dietary SBM intake on red seabream metabolism.