Development of novel tumor-targeted drug vehicles for cancer therapy is very important and has become one of major topics for designing nanoscale chemotherapeutics delivery systems. In the present study, selenium nanoparticles (SeNPs) was decorated with hyaluronic acid (HA) to prepare HA-SeNPs nanoparticles which were used to load doxorubicin (DOX) to fabricate tumor-targeted functionalized selenium nanoparticles HA-Se@DOX. In vitro and in vivo antitumor activities of HA-Se@DOX in human cervical carcinoma treatment were investigated. HA-Se@DOX showed selective cellular uptakes between cervical cancer HeLa cells and human umbilical vein endothelial cells (HUVEC). In vitro release result indicated that DOX was released from HA-SeNPs faster in acidic environment in comparison with normal physiological environment and 76.9% DOX was released in pH 5.4 during initial 30 h. HA-Se@DOX showed high activity to inhibit HeLa cell proliferation and triggered HeLa cell apoptosis via activating Bcl-2 signaling pathway. In vivo antitumor study showed that HA-Se@DOX inhibited tumor growth through suppressing cancer cells proliferation and inducing cancer cells apoptosis. Interestingly, HA-Se@DOX exhibited stronger anticancer activity than free DOX and Se@DOX in vitro and in vivo. Additionally, HA-Se@DOX did not cause damage to major organs at the used dose. HA-Se@DOX is a promising antitumor agent for human cervical carcinoma treatment and this research provides a novel therapeutic strategy for cancer therapy. •Novel functionalized nanoparticles HA-Se@DOX for delivery of doxorubicin with anticancer activity.•HA-Se@DOX efficiently deliver doxorubicin without cytotoxicity.•HA-Se@DOX shows selective cellular uptake between HeLa cervical carcinoma cells and human normal cells.•HA-Se@DOX exhibit great antitumor efficacy in HeLa cervical carcinoma tumor model.