7-Ethyl-10-hydroxy-camptothecin (SN-38), an efficient topoisomerase inhibitor, is the biological metabolite of irinotecan used as the first-line chemotherapy drug for colon cancer. However, the hydrophobicity and instability of SN-38 limit its further clinical application. In this study, to improve water dispersity and the anti-tumor efficiency of SN-38, a prodrug, SN-38-BOC, that could efficiently transform to active SN-38 in the acidic tumor microenvironment was synthesized and encapsulated into MPEG-P(CL-ran-TMC) micelles (SN-38-BOC micelles). SN-38-BOC micelles could accumulate in tumors due to the EPR effect and exhibit a sustained release behavior, which was rapidly transformed to active SN-38 by the acidic environment of tumor tissues (pH 5.5-6.8), thus achieving efficient anti-tumor activity. Compared with the free SN-38-BOC group, enhanced cytotoxicity and apoptotic induction were obtained from the SN-38-BOC micelle-treated group in both HCT116 and CT26 cells. In addition, SN-38-BOC micelles showed more effective anti-angiogenesis than free SN-38-BOC in a transgenic zebrafish model. Furthermore, SN-38-BOC micelles exhibited stronger inhibition of tumor growth in both HCT116 and CT26 subcutaneous xenograft tumor models. Histological analysis revealed that SN-38-BOC micelles showed a more effective anti-tumor activity than the free drug by inducing more apoptosis, inhibiting angiogenesis, and suppressing proliferation. Thus, the pH-activatable SN-38-BOC micelle could serve as a promising candidate in colorectal tumor therapy.