<p>Lumbar disc herniation (LDH) is a complex degenerative disease caused by inflammation and mechanical compression of nerve roots by the nucleus pulposus (NP). Astragalus polysaccharides (APS) have anti-inflammatory and immunomodulatory effects. Given the regulatory role of O-GlcNAcylation in inflammation and degenerative diseases, this study aimed to explore the potential molecular regulatory mechanism of O-GlcNAcylation in the anti-inflammatory effect of APS in LDH. We established the LDH rat model to investigate the effects of APS on LDH and inflammatory response. IL-1β-stimulated NP cells were generated, and inflammation was assessed by measuring the expression of IL-6, IL-18, and TNF-α with enzyme-linked immunosorbent assay. The apoptosis of NP cells was analyzed by flow cytometry. The underlying mechanism was investigated by quantitative real-time PCR, co-immunoprecipitation, and molecular docking. The results indicated that APS inhibited proinflammatory cytokine expression in LDH rats and IL-1β-induced NP cells. APS bonded to OGT and promoted its mediated-O-GlcNAcylation levels. Further, we certified that NRF2 was the target of OGT-mediated O-GlcNAcylation. Of note, the silencing of NRF2 abolished the protective effects of OGT on IL-1β-stimulated NP cells. The mitigation effect of APS on LDH is through enhancing OGT expression to promote O-GlcNAcylation of NRF2, suggesting that O-GlcNAcylation of NRF2 is an important regulatory factor for LDH and offers a novel treatment strategy for the disease.</p>