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Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound <b>4b</b> exhibited most excellent anti-proliferation activities against SW620 cells with IC₅₀ of 0.86 &#177; 0.02 &#181;M than Celecoxib (IC₅₀ = 1.29 &#177; 0.04 &#181;M). The results favored our rational design intention and provides compound <b>4b</b> as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.