In the following study, we describe the preparation and characterization of poly(ethylene glycol) (PEG) and biotin modified, doxorubicin (DOX) loaded silica nanoparticles (Dox/SLN-PEG-Biotin), which was employed as a drug delivery system for colon cancer therapy. The DOX/SLN-PEG-Biotin exhibited small particle size and low cytotoxicity in vitro. Moreover, the Dox releases from DOX/SLN-PEG-Biotin followed a redox-sensitive behavior. Biotin functionalized Dox/SLN-PEG-Biotin demonstrated tumor-targeted delivery of their payload, resulting in enhanced cellular uptake in HCT116 tumor cells and potentiated tumor accumulation in HCT116 tumor-bearing mice. In particular, in vivo anti-cancer assay confirmed that DOX/SLN-PEG-Biotin as a tumor-targeted delivery system exerted strong anti-cancer efficacy. Altogether, DOX chemotherapy using DOX/SLN-PEG-Biotin might be an effective strategy for improved treatment in colon cancer.