Objective To investigate the characteristics of macrophage depletion by clodronate liposomes (CL) in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and analyze transcriptomic features. Methods: Thirty-two C57BL/6 mice were randomly divided into the blank liposome group (CL) and the clodronate liposome group (PL), with 16 mice in each group, receiving intraperitoneal injections of CL or PL. On the 5th day, each group was further divided into control (-N) and model (-M) subgroups, with 8 mice per subgroup. The model group was given 10% CCl4 intraperitoneally to induce liver fibrosis, while the control group received an equal volume of olive oil. After 4 weeks, serum ALT and AST levels were measured; liver inflammation and collagen deposition were observed via HE and Sirius Red staining. RNA was extracted from liver tissues for high-throughput transcriptome sequencing and differential gene expression analysis. Results: Serum ALT and AST levels were significantly elevated in the PL-M group, with fibrosis staging primarily at S3. In the CL-M group, fibrosis staging was primarily at S1. A total of 1,462 and 2,119 differentially expressed genes (|logFC| > 2 and P < 0.05) were identified in the PL and CL groups, respectively. GO analysis revealed enrichment in multiple biological processes, cellular components, and molecular functions in both models. KEGG analysis identified 29 significantly enriched pathways (P < 0.05). RT-qPCR validated the upregulation of genes such as Lgals7 and Timp1 and the downregulation of Mup-ps16 and Mup15, consistent with transcriptomic trends (P < 0.05). Conclusion: This study highlights the characteristics and transcriptomic features of macrophage depletion in the CCl4-induced liver fibrosis model, providing a theoretical reference for research on the immune mechanisms of liver fibrosis.