Objective To explore the protective effect of polydatin and its mechanism on secondary liver injury in silicosis rats based on network pharmacology and animal experiments. Methods i) Network pharmacology study. Based on multiple databases, the targets of polydatin effect related to silicosis and liver injury were collected, and the common targets of polydatin-silicosis-liver injury were screened to construct a protein-protein interaction network. Enrichment analyses were performed to identify core targets involved in the effects of polydatin on silicosis-associated secondary liver injury. The mechanism of action of polydatin in relieving silicosis and silicosis-associated secondary liver injury was investigated, in which polydatin served as molecular docking ligand. ii) Animal experimental validation. Specific pathogen free male SD rats were randomly divided into three groups, with 10 rats per group. Rats in the model and intervention groups received 1 mL of a silica suspension at a mass concentration of 50 g/L for modeling using a one-time non-tracheal exposure method. Then rats in the intervention group were injected intraperitoneally with polydatin solution at 30 mg/kg body weight, once daily starting from the first day after silica exposure, whereas rats in the control group received no treatment. Lung and liver histopathology of rats, which were randomly sacrificed on days 28 and 56 post-exposure in both groups, were examined. Biomarkers of liver injury and hepatic oxidative stress were measured, and hepatic expression of nuclear factor erythroid 2-related factor 2 (NRF2) related proteins was detected by Western blotting. Results i) Network pharmacology study results. A total of 137 polydatin-related targets, 14 812 silicosis-related targets, and 3 038 liver injury-related targets were identified, among which 69 were common targets and 28 were key targets. Gene Ontology analysis indicated that the key targets were involved in 1 883 pathways. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified 137 pathways related to the targets. Molecular docking showed good binding affinities between polydatin and B-cell lymphoma 2 (BCL2), interleukin 6 (IL-6), tumor necrosis factor (TNF), and NRF2. ii) Animal experimental validation results. Compared with the control group, rats in the model group showed increased collagen deposition in both lung and liver tissues, with hepatic degeneration, necrosis, and inflammatory cell infiltration on days 28 and 56 after silica exposure. The collagen in lung and liver tissues of rats on days 28 and 56 after silica exposure increased in the model group compared with the control group (all P<0.05). Meanwhile, serum alanine aminotransferase and aspartate aminotransferase activities, hepatic lactate dehydrogenase 5 activities and NADPH: quinone oxidoreductase 1 (NQO1) expression in liver tissue increased (all P<0.05), whereas hepatic superoxide dismutase activity and NRF2 expression were decreased (all P<0.05). The level of malondialdehyde and the relative expression of heme oxygenase-1 (HO-1) protein in liver tissue in rat of model group were higher than those in the control group (all P<0.05). These alterations were ameliorated in rats of the intervention group compared with the model group (all P<0.05). Conclusion Polydatin exerts protective effects against secondary liver injury in rats with silicosis. These effects may be mediated by regulation of core targets such as BCL2, IL6, TNF, and NRF2, modulation of inflammatory pathways including TNF and IL17 signaling, and activation of the NRF2/HO-1 pathway, thereby exerting synergistic anti-inflammatory, antioxidant, and antifibrotic effects via the "lung-liver axis".