The inflammatory bowel disease (IBD) is a multifactorial disorder and complex. Previous studies have shown that Cleistocalyx operculatus Roxb. Merr. et Perry and Morus alba L. have anti-inflammatory properties. This study aims to evaluate the effects of combined Cleistocalyx operculatus Roxb. Merr. et Perry and Morus alba L. (CM) extracts on dextran sulfate sodium (DSS)-induced acute colitis in mice. The combined Cleistocalyx operculatus Roxb. Merr. et Perry and Morus alba L. leaves were extracted with 50% ethanol and then suspended in water and partitioned successively with ether and ethyl acetate. The ethyl acetate extract was combined and evaporated to obtain CM extract. Mice were induced colitis, by using DSS for seven days. Mice were treated with combined CM extracts at doses of 150 mg/kg/b.w. and 300 mg/kg/b.w. Throughout the experiment, the disease activity index (DAI) was evaluated. Following the last day of treatment, blood samples were collected for analysis of IL-1β, INF-γ and TNF-α by using a sandwich enzyme-linked immunosorbent assay (ELISA) method. The CM extract significantly decreased the disease activity index and myeloperoxidase activity in the CM extract-treated mice as compared with DSS group mice. The combined CM extracts also suppressed the levels of pro-inflammatory IL-1β, INF-γ and TNF-α in colon tissues of the CM extract-treated mice as compared with DSS group (p < 0.05). Our results showed that the combined CM extract has strong beneficial effects on colitis and could be used for the treatment of IBD.