Polygonatum sibiricum has long been a popular functional food in Asia, known for its anti-inflammatory properties. However, its efficacy in alleviating colitis has yet to be investigated. This study aimed to explore the therapeutic potential of P. sibiricum polysaccharides (PSP) in dextran sulfate sodium (DSS)-induced colitis, focusing on the related pyroptosis mechanisms. Scanning electron microscopy (SEM) analysis showed that PSP possesses a smooth surface with no pore structure and a dense, lamellar structure adorned with numerous spherical entities. PSP treatment significantly reduced colitis symptoms and decreased pro-inflammatory cytokines, likely through suppression of the Toll like receptor 4 (TLR4)/nuclear factor κB (NF-κB) signaling pathway. Additionally, PSP attenuated NOD-like receptor protein 3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase-1/Gasdermin D (GSDMD)-mediated pyroptosis and mitochondria damage in the colon, while enhanced the expression of tight junction and adherens junction proteins. Microbiota sequencing showed that PSP increased the abundance of phylum Bacteroidota and genus such as g_unclassified_f_Muribaculaceae, Lactobacillus, Clostridia_UCG-014, and Lachnospiraceae_NK4A136_group, while decreased the phylum Proteobacteria and the genus Enterobacter, Escherichia-Shigella, and Blautia. In conclusion, this study demonstrates that PSP exerts the potential therapeutic role against colitis, which was mediated by the regulation of gut microbiota and the inhibition of colonic NLRP3/ASC/Caspase-1/GSDMD signaling pathway.