In this study, a series of novel ibuprofen (Ibu) hybrid molecules with aminothiazole heterocycles were designed, synthesized and evaluated for their anti-inflammatory potency in vitro and in vivo. Among all these derivatives, compounds 6 and 8 effectively inhibited the production of NO (with 87 %, 79 % NO-inhibitory rates, respectively) with minimal cytotoxic effect in RAW 264.7 macrophages. Anti-inflammatory mechanism studies revealed that representative compound 6 dose-dependently inhibited pro-inflammatory cytokines by blocking the activation of NF-kappaB signaling pathway in LPS stimulated RAW 264.7 macrophages. In vivo experiments showed that 10 mg/kg compound 6 had a good improvement effect in DSS-induced mouse acute colitis compared to Ibu. Our findings will provide new insights into the development of new drugs with anti-inflammatory functions.