Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. However, there is no effective chemotherapeutic treatment for HCC and its prognosis remains poor. Consequently, it is urgent to find an efficient antitumor agent to treat HCC. In this study, 7-ethyl-10-hydroxycamptothecin (SN38), the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100-1000 times more potent than CPT-11, was coupled with aspirin to give 4 prodrugs. Their structures were characterized by H-1 NMR and elemental analysis. The in vitro anticancer activities of these compounds on two human hepatocellular carcinoma cell lines (BEL-7404 and HepG2) and preliminary mechanisms of action were explored. Our data indicated that these compounds decreased the viability of cancer cell lines in a concentration- and time-dependent manner. Among them, compound 4b significantly inhibited cell viability of HepG2 cells (IC50 = 0.1208 mu M) when compared with CPT-11 (IC50 = 18.4267 mu M). Furthermore, compound 4b blocked HepG2 cell migration and invasion in vitro. These findings suggest that compound 4b may be used as a promising anticancer agent against HCC.