Background: Luteolin-7-O-glucoside (Lut-7-G) is an effective compound found in plants, such as Patrinia and honeysuckle. It has anti-inflammatory as well as antioxidant properties; however, its anti-inflammatory effect on ulcerative colitis (UC) is hardly understood. Objectives: We evaluated the effects of Lut-7-G in dextran sodium sulfate (DSS)-induced UC in mice models, and then explore the underlying mechanism by studying the JAK1/STAT6/SOCS1 signaling pathway. Materials and Methods: Induction of acute colitis in mice was achieved by feeding 2.5% DSS for 7 days. Bodyweight loss, colon length, disease activity index (DAI) score, and spleen index were determined and hematoxylin-eosin and Periodic Acid-Schiff staining were performed to study the pathological changes in mouse colons. The inflammatory factor levels were determined by ELISA, JAK1, STAT6, and SOCS1 expression in colon tissues by RT-qPCR, and signaling pathway proteins by Western blotting. Results: It was found that treatment with Lut-7-G reduced the effects of colon shortening and weight loss, DAI score, spleen index, as well as colon inflammation. In addition, it significantly decreased DSS-induced overexpression of IL-6, IL-1β, IL-18, as well as TNF-α, and considerably reduced mRNA expression of JAK1 and STAT6 but upregulated the SOCS1 expression. Furthermore, Lut-7-G treatment dose-dependently decreased JAK1 and STAT6 protein expression, and only DSS + Lut-7-G (100 mg/kg) could downregulate p-JAK1 and p-STAT6 expression and upregulate SOCS1 protein expression. Moreover, Lut-7-G (100 mg/kg) was as effective as mesalazine. Conclusion: Lut-7-G may regulate the secretion of inflammatory factors and inhibit inflammatory responses through the JAK1/STAT6/SOCS1 pathway, as a determinant in the treatment of UC.