Silicosis is a pulmonary disease characterized by inflammation and progressive fibrosis. Previous studies have shown that polydatin (PD) has potential biological activity in key signaling pathways regulating inflammation and apoptosis. To investigate the effect of PD on rats with silicosis, this study used network pharmacology and molecular docking methods to determine the target of PD treatment for silicosis. The therapeutic effect of PD on silicosis was confirmed by measuring the lung injury score, hydroxyproline content, and mRNA expression levels of key targets. In addition, metagenomic sequencing and gas chromatography-mass spectrometry were used to determine the gut microbiota composition and targeted metabolomics analysis, respectively. The results showed that PD could inhibit the expression of inflammation-related indexes and apoptosis-related indexes at protein and mRNA levels. PD also regulates the diversity of the intestinal flora and the content of short-chain fatty acids. In conclusion, the current data suggest that PD has a protective effect against silica-induced lung injury and plays a protective role in regulating intestinal flora diversity and short-chain fatty acid levels through the gut-lung axis.