Ulcerative colitis (UC), a bowel disease with significant morbidity, is associated with inflammation. In this study, the effect of Qingchang Huashi granule (QCHS) on UC and its underlying mechanisms were explored using both animal and cell culture experiments. A rat UC model was induced with trinitro-benzene-sulfonic acid (TNBS), concentrations of the cytokines IL-1α, IL-6, IL-8, IL-1β, and TNF-α were significantly up-regulated and the concentrations of IL-4, IL-10, and IL-13 were significantly down-regulated compared with the control group (P < 0.05). In contrast, the QCHS and salicylazosulfapyridine (SASP) groups reversed these modulations (P < 0.05). A UC cell model in HT-29 cells was generated using TNF-α combined with lipopolysaccharide treatment. Cells treated with QCHS were used to investigate the possible mechanisms. The expression of apoptosis-related proteins, including Bax/Bcl-2, caspase-3, caspase-9, Fas/Fas-L, and Rafl in the QCHS and SASP groups, were significantly lower than that in the control group in both animal and cell experiments (P < 0.05). In addition, the in vitro results indicate changes in these indicators mediate the MEK/ERK signaling pathways via SGK1. Our results suggested that QCHS could be beneficial in preventing UC progression as an alternative drug for UC treatment.