Curcumin (Curcuma longa L), a yellow-colored Indian spice, receives immense attention for the prevention and treatment of various cancers. Despite the superlative therapeutic efficacy, its poor solubility and instability in the aqueous medium hinder the effectiveness of cancer treatment. The novel preparation of curcumin nanoparticles by mechanical grinding of curcumin crystals without any toxic organic solvents is described here for the first time. The surface of curcumin nanoparticles is modified with the negatively charged polyelectrolyte poly(sodium 4-strynesulfonate) through hydrogen bonding, which is the key to increasing the solubility and stability in the aqueous medium. The negative surface charge is exploited to conjugate doxorubicin drug molecule on the surface of curcumin nanoparticles as evidenced by fluorescence quenching experiments. Doxorubicin-conjugated curcumin nanoparticles have a higher solubility with an enhanced cytotoxic effect toward the human hepatocellular carcinoma cell line by a reactive oxygen-species-mediated p53-dependent apoptotic pathway. The combination of chemotherapy and photodynamic therapy significantly enhances antitumor activity of doxorubicin-conjugated curcumin nanoparticles, and is expected to be a promising anticancer agent with special reference to human liver carcinoma cells.