Objective <p>Resveratrol glycoside (also known as polydatin, PLD), known for its anti-inflammatory and anti-fibrotic properties, has shown potential in mitigating fibrosis in various organs. This study aimed to investigate the effects of PLD on high glucose-induced peritoneal fibrosis and its underlying mechanisms, focusing on the NOD-like receptor protein 3 (NLRP3)/interleukin-1 beta (IL-1β)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling.</p> Methods <p>Eighteen Sprague–Dawley rats were divided into three groups: control, peritoneal fibrosis, and resveratrol glycoside treatment. Histological and immunohistochemical analyses were performed to assess peritoneal fibrosis. Human peritoneal mesothelial cells (HMrSV5) were treated with high glucose and PLD to evaluate cell morphology, viability, and the expression of fibrosis and inflammatory markers via Western Blot and immunofluorescence.</p> Results <p>PLD significantly reduced peritoneal fibrosis in rats, as evidenced by histological analyses showing decreased tissue thickness and collagen deposition. It also downregulated the expression of transforming growth factor beta 1 (TGF-β1), collagen type I (Col I), alpha-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), NLRP3, phosphorylated p65 subunit of NF-κB (p-p65), IL-1β, interleukin-18 (IL-18), cleaved caspase-1 p20 subunit (caspase-1p20) and ROS level, while upregulating E-cadherin. In HMrSV5 cells, PLD mitigated high glucose-induced epithelial-mesenchymal transition, angiogenesis, reactive oxygen species (ROS) production and inflammation, which was reversed by overexpression of NLRP3, suggesting the involvement of the NLRP3/IL-1β/NF-κB pathway.</p> Conclusion <p>PLD alleviates high glucose-induced peritoneal fibrosis, angiogenesis, ROS production and inflammation by inhibiting the NLRP3/IL-1β/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for peritoneal fibrosis.</p>