Objective To assess transcriptomic differences between carbon tetrachloride ( CCl₄ )-induced and diethyl 1,4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate ( DDC) diet-induced mouse models of liver fibrosis to provide a framework for future research using mouse liver fibrosis models. Methods Mouse models of liver fibrosis were induced by a 10% CCl₄(2 mL/ kg) injection or a 0. 1% DDC diet. After 4 weeks of induction, serum levels of ALT, AST,and TBil were measured. HE and Sirius red staining were used to observe hepatic inflammation and collagen deposition.Jamall’ s method was used to evaluate hydroxyproline ( Hyp) content in liver tissues. Hepatic tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were measured by ELISA. Total RNA was extracted from murine liver tissues for RNA-sequencing (RNA-seq). Differentially expressed genes of the two models were analyzed by R software and then GO and KEGG enrichment was performed. Then, genes with significant differences were verified. Results Compared with normal mice, serum levels of ALT, AST, and TBil and hepatic expression of TNF-α, IL-6, and IL-1β were significantly increased in mice that received CCl₄ and DDC, while the Alb serum level was decreased. Pathological staining showed that the structures of liver tissues were destroyed and a large number of hepatocytes around the central vein were hyalinized and necrotic in CCl₄ -treated mice. In DDC diet-treated mice, a large amount of porphyrins had been deposited in the liver and a large number of inflammatory cells had infiltrated into the portal area and bile duct. Different degrees of collagen deposition were observed in the liver tissues of the two model mice. Different genes (DEGs) of CCl₄- and DDC diet-treated mice were screened using a filter (| logFC | > 2-fold and P<0. 05). As a result , 1820 and 2373 DEGs in CCl₄- and DDC diet-treated mice were analyzed, including 1302 and 1978 upregulated genes, and 518 and 395 downregulated genes,respectively. GO annotation showed that the two models had important functions in molecular function, biological process,and cell component. KEGG analysis showed that 22 and 29 signaling pathways were activated in CCl₄- and DDC dietinduced models, respectively. Among them, 16 signaling pathways, such as extracellular matrix receptor interaction, cell cycle, protein digestion and absorption, focal adhesion, and PI3K-Akt, were significantly enriched in the two models (P<0. 05). Cluster analysis showed that Mup11, Mup15, Mup17, and Mup1 were significantly down-regulated in both models,which were identified by RT-qPCR (P<0. 05). Conclusions This study conducted a comparative analysis of the RNASeq transcriptomic features of liver fibrosis models induced by exposure to CCl₄ and a DDC diet. It examined the gene expression patterns and the pathways influenced by gene expression. The findings serve as a valuable resource for selecting appropriate animal models for future research on the pathogenesis and treatment of liver fibrosis.