Ulcerative colitis (UC) is a type of human intestinal disease with limited therapeutic options and a low cure rate. The difficulty in treating UC is partly attributed to its complex immune regulatory mechanisms. Artemether, a derivatives of artemisinin, has shown significant therapeutic potential in treating immune-related diseases, such as systemic lupus erythematosus and atherosclerosis. This study aimed to explore the potential ameliorative effects and mechanisms of artemether in UC mice. Through in vivo and in vitro experiments, we found that artemether improved colon inflammation and intestinal barrier dysfunction in mice by decreasing the levels of inflammatory factors IL-1beta and IL-6, promoting the upregulation of tight junction proteins ZO-1 and Occludin, and inhibiting intestinal leakage. These effects may be mediated by regulating Notch signaling activation and suppressing pro-inflammatory M1 macrophages. This discovery provides new potential therapeutic strategies for colitis.