Sinomenine is extracted from the root of Chinese herb QingTeng (Sinomenium acutum (Thunb.) Rehd. Et wils.), which is extensively utilized by traditional medical practitioners for its anti-inflammatory and immunoregulatory properties in China for decades. The aim of this study was to assess the effects and potential mechanisms of sinomenine in alleviating dextran sodium sulfate (DSS)–induced chronic colitis and memory disorder in mice. A mouse chronic colitis model was established by 2.5% DSS, and sinomenine treatment was oral administration. It showed that sinomenine inhibited weight loss, colon shortening, proinflammatory cytokine production, and intestinal barrier injury in the colon. Sinomenine improved inflammatory bowel diseases (IBD) and accompanying memory disorders with downregulated expressions of proinflammatory cytokines and neuronal apoptosis; upregulated expressions of brain-derived neurotrophic factor (BDNF) and ZO-1 in the hippocampus. Additionally, our findings indicated that sinomenine altered the composition of various gut microbiota, leading to an increase in Bacteroidetes and Firmicutes at the phylum level, and Rikenella at the genus level. Moreover, sinomenine ameliorated the SCFA content in DSS-induced mice both in serum and feces. The findings demonstrated that sinomenine ameliorated DSS-induced chronic colitis and accompanying memory disorders.