Objective Compare the differences in serum biochemistry,pathology, and transcriptomics of metabolic dysfunction-associated steatohepatitis (MASH) models caused by carbon tetrachloride combined with a high-fat diet (CCl4 high-fat group) and methionine-choline-deficient diet (MCD group). Methods CCl4 high-fat and MCD models were respectively used to measure serum ALT and AST levels, as well as liver tissue inflammatory factors such as IL-1β, IL-6, IL-10, and TNF-α, serum/liver tissue TC and TG contents were detected. HE staining, Sirius Red staining, Oil Red O staining, and α-SMA immunohistochemistry were used to observe the degree of liver inflammation, fat infiltration, and fibrosis staging. Total RNA was extracted from the liver tissues for sequencing analysis (RNA-Seq). Differential genes from the two models were subjected to GO and KEGG enrichment analysis, followed by validation with qRT-PCR. Results Compared with normal mice, the levels of ALT, AST and the contents of TC, TG, IL-1β, IL-6 and TNF-α in the two types of model mice were significantly increased, while IL-10 levels decreased; pathological staining results indicated that the livers of mice in both model groups showed inflammatory infiltration, destruction of liver lobule structure, a significant increase in lipid droplets in the liver tissue, steatosis, and collagen deposition. Among them, collagen deposition was more pronounced in the CCl4 high-fat model group, while inflammatory changes were more obvious in the MCD model group. By screening with the criteria (| log2FC | > 1 and P < 0.05), the high-fat CCl4 group and the MCD group were found to have 2,819 and 2,069 differential genes, respectively. KEGG enrichment analysis revealed that 88 and 75 pathways were activated in the CCl4 high-fat model and MCD model groups, respectively, with 33 pathways activated in both. Cluster analysis of intersecting genes showed that the two models shared 916 intersection genes. Genes such as Cyp2a4, Gpnmb, and Cyp2a22 were significantly upregulated in both models, while Mup3, Mup7, and Slco1a1 were significantly downregulated in both models. RT-qPCR validation was consistent with the transcriptome sequencing results. Conclusion The above two models exhibit MASH disease features while each has its own characteristics. Among them, 'enhanced detoxification stress, decreased synthetic function, and initiation of inflammation-fibrosis' are the core molecular features of MASH; the pathological phenotype of the CCl4 high-fat model centers on inflammatory damage, with KEGG enrichment in inflammatory and fibrotic pathways such as the PI3K-Akt signaling pathway, ECM-receptor interaction, and focal adhesion; the MCD model, on the other hand, more prominently shows pathological features of metabolic imbalance, with KEGG enrichment in lipid metabolism pathways such as retinol metabolism, glutathione metabolism, and steroid hormone biosynthesis.