Objective To investigate the characteristics of macrophage depletion by clodronate liposomes (CL) in a carbon tetrachloride (CCl₄ )-induced liver fibrosis mouse model, and to analyze the transcriptomic features. Methods Thirty-two C57BL/6 mice were divided randomly into plain control liposomes for clophosome (PL) and clodronate liposome (CL) groups (n=16 mice per group), and administered intraperitoneal injections of PL and CL, respectively. On day 5, each group was further divided into normal (N) and model (M) subgroups (n=8 mice per subgroup). Mice in group M received 10% CCl4 intraperitoneally to induce liver fibrosis, while mice in group N received an equal volume of olive oil. After 4 weeks, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured, and hepatic inflammation and collagen deposition were evaluated by hematoxylin/eosin and Sirius red staining, respectively. Total RNA was extracted from liver tissues for transcriptomic sequencing and subsequent differential gene expression analysis. Results Serum ALT and AST levels were significantly elevated in the PL-M group(P<0.01), with fibrosis staging primarily at S3, compared with S1 in the CLM group. Totals of 1462 and 2119 differentially expressed genes (|log fold change|>2 and P<0.05) were identified in the PL and CL groups, respectively. Gene Ontology analysis revealed enrichment in multiple biological processes, cellular components, and molecular functions in both models, and Kyoto Encyclopedia of Genes and Genomes analysis identified 29 significantly enriched pathways (P<0.05). The upregulation of genes including Lgals7 and Timp1 and the downregulation of Mup-ps16 and Mup15 were validated by reverse transcription-quantitative polymerase chain reaction, consistent with transcriptomic trends (P<0.05). Conclusions 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.