In the United States, colorectal cancer (CRC) is the second most frequent malignancy and the fourth most common cause of cancer death. Baicalin, a flavone derivative isolated and purified from the dry root of Scutellaria, was assessed for its antitumor effects in human SW620 CRC cells. Baicalin (200 μM) inhibited proliferation of SW620 cells. Baicalin (200 μM) increased activities of caspase-3, -8, and -9 in SW620 cells. Furthermore, flow cytometric analysis of baicalin-treated SW620 cells showed an increase in sub-G1 cells, and the dihydroethidium assay showed significant enhancement of intracellular peroxide production in baicalin-treated cells. Addition of N-acetylcysteine prevented most of the baicalin-induced apoptosis, which in turn mediated cytotoxicity in human SW620 cells. In vivo, baicalin (50 mg/kg/day, i.p.) treatment inhibited 55% of tumor growth in xenografted nude mice by 4 weeks, compared to that of the vehicle control (p < 0.05). Baicalin had no noteworthy influence on body weight. Thus, we suggest the development of baicalin as a potential leading antitumor agent in CRC.