Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Due to its poor response to conventional chemotherapy drugs, the prognosis for its survival is the worst. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an attractive anticancer target due to its overexpression in HCC. Although triptolide (TP) possesses potent antitumor activity, its clinical practice is greatly limited due to its general toxicities and narrow therapeutic window. Herein, we develop an NQO1-selective activated TP analog, named CX-23, which exhibited antiproliferation of HepG2 over normal hepatocytes in vitro. In vivo study shows that CX-23 can not only prevent the hepatocellular carcinoma progression but also migrate the liver and kidney toxicity. These findings indicate that NQO1 may serve as a targeted delivery system to release an antitumor reagent and that CX-23 may be a promising lead for developing targeted antihepatocellular carcinoma drugs.