Objective To compare the 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 in order to provide a framework for future research utilizing mouse liver fibrosis models. Methods Mouse models of liver fibrosis were induced by 10%CCl4 (2ml/kg) injection and 0.1%DDC diet, respectively. After the 4 -week induction, the serum levels of ALT, AST, and TBil were detected. HE and Sirius red staining were observed to analyze the hepatic inflammation and collagen deposition. Jamall's method was used to evaluate the hydroxyproline (Hyp) content in the liver tissues. Hepatic tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by the elisa kits. Total RNA was extracted from murine liver tissues for RNA sequencing (RNA-Seq). The differentially expressed genes of the two models were analyzed by R software and then GO and KEGG enrichment were analyzed. Then, cwas used to verify the significantly different genes. Results Compared with normal mice, the serum levels of ALT, AST, TBil and the expressions of hepatic TNF-α, IL-6 and IL-1β were significantly increased in mice received CCl4-induction and DDC diet mice respectively, while the serum level of Alb 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 mice, a lot of porphyrins were deposited in the liver and a large number of inflammatory cells were infiltrated in the portal area and the bile duct. Different degrees of collagen deposition were observed in the liver tissues of the two model mice. Different genes(DEGs) of CCl4-treated and DDC-diet mice were screened according to a filter (|logFC|> 2 times and P < 0.05). 1820 and 2373 DEGs in CCl4-treated and DDC-diet were analyzed, including 1302 and 1978 up-regulated genes , 518 and 395 down-regulated genes, respectively. GO annotation showed that the two models had important functions in molecular function (MF), biological process (BP) and cell component (CC). KEGG analysis showed that 22 and 29 signaling pathways were activated in CCl4-induction and DDC diet model, respectively. Among these, 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, Mup1 were significantly down-regulated in both models, which were identified by RT-qPCR (P < 0.05). Conclusions This study reported and compared the RNA-Seq transcriptomic characteristics of liver fibrosis models induced by CCl4-induction and DDC-diet, respectively. By observing the locations of gene expression and the pathways regulated by the genes, an example was established for the subsequent selection of animal models to study the pathogenesis and treatment of liver fibrosis.