Resveratrol (RES) is a polyphenolic antioxidant derived from different plant products, which has anti-inflammatory and antioxidative stress effect. However, the effect of resveratrol on chronic rhinosinusitis (CRS) still lacks systematic research. This study aims to elucidate the potential mechanism of resveratrol against CRS disease through network pharmacology and further verify it through biological experiments in human nasal epithelial cells (HNEpCs). The potential targets and pathways of RES against CRS disease were predicted by network pharmacology and molecular docking. Furthermore, the inflammation of HNEpCs was induced by lipopolysaccharide (LPS). The method of ELISA was used to detect changes in inflammatory factors and oxidative stress-related factors. The RT-qPCR method was adopted to analyze the changes of genes in related signaling pathways. As a result, 33 potential targets related to the effect of RES against CRS disease were obtained. According to the results of network pharmacology, it was shown that the effect of RES against CRS disease was closely related to the inflammation, oxidative stress, and apoptosis. A variety of results from cell experiments verified that RES can effectively inhibit the inflammation, oxidative stress and apoptosis of LPS-induced HNEpCs. Together, the present study systematically clarified the possible mechanisms of RES in the treatment of CRS and provided new ideas for the drug research of this disease.© 2025 John Wiley & Sons Ltd.