Ethnopharmacological relevance: HuanglianGanjiang Tang (HGT) is a classic prescription of traditional Chinese medicine (TCM) recorded in Dan Xi Xin Fa, which was used to alleviate manifestations like diarrhea, abdominal pain and hemafecia. In current clinical practices, HGT is adopted for the treatment of ulcerative colitis (UC) and affords good curative effect. However, the underlying mechanism deserves further elucidation. Aim of the study: UC is a hard-to-curable and easy-to-recurrent inflammatory disease. This study is to evaluate the potential therapeutics and explore the molecular mechanism of HGT on UC in the mouse model. Materials and methods: The components of HGT extracts were identified by HPLC. The colitis of mice was induced by 3% (w./v.) dextran sulfate sodium (DSS). The HGT decoction was prepared through boiling and centrifuging. The mice were given HGT decoction via oral gavage (0.34 g/ml & 0.68 g/ml; 5 ml/kg b.w.). The protective role of HGT on colitis mice was evaluated by body weight change, colon length, disease activity index (DAI) and histological scores. The expressions of necroptosis-related and vitamin D receptor (VDR)-related proteins were measured by Western blot, RT-qPCR and immunofluorescence.Results: HGT could significantly reduce the loss of body weight and colon length in colitis mice, and alleviated the DAI and histological scores. Mechanically, HGT also promoted the expression of E-cadherin, Occludin, ZO-1 and VDR, and reduced the level of intestinal inflammatory cytokines, such as, IL-6, IL-1 beta and TNF-alpha. Besides, HGT downregulated the protein level of p-RIPK3, p-RIPK1 and p-MLKL while upregulated the protein level of Caspase-8 in colon tissue compared to the model group. Conclusion: Our study addressed that HGT can alleviate DSS-induced colitis of mice through inhibiting colonic necroptosis by upregulating the level of VDR.