Silver nanoparticles (AgNPs)embedded poly (N-vinylpyrrolidone/dextran) hydrogels were prepared by gamma radiation. Highly stable and uniformly distributed AgNPs have been obtained within hydrogel networks as nanoreactors via in situ reduction of silver nitrate using sodium borohydride as reducing agent. The formation of AgNPs has been confirmed by Fourier transform infrared spectroscopy. The ultraviolet–visible spectroscopy measurements show a distinct characteristic absorption peaks around 420 nm, indicating the formation of AgNPs. X-ray diffraction analysis and dynamic light scattering demonstrated that the hydrogels have regulated the AgNPs size to a nanoscale. The combination of the AgNPs with doxorubicin (DOX) as a model of antitumor drug forms a new biocompatible nanodrug. Our results show that the AgNPs effectively increased survival rate and decreased tumor volume of Ehrlich ascites carcinoma–bearing mice more than the DOX-treated group and enhanced the cytotoxicity of DOX in different human cancer cell lines (HepG2, T47D, and PC3). DOX-AgNPs decreased malondialdehyde and total nitrate/nitrite levels and increased superoxide dismutase activity and glutathione content in the rat cardiac tissues compared with the DOX-treated group. In conclusion, DOX-AgNPs improved therapeutic index and reduced DOX-induced cardiotoxicity via preservation of cardiac markers, which represents a promising candidate for cancer treatment.