In summary, this study elucidated the efficient protective role of ruscogenin against DSS-induced colitis and demonstrated that ruscogenin alleviates DSS-induced colitis in mice by inhibiting NLRP3 inflammasome activation and caspase-1-dependent canonical pyroptosis, probably due to the suppression of the TLR4/NF-κB signaling pathway. The gene discussed is NFKB1; the disease is colitis.