The current study aimed at preparing AgNPs and three different core-shell silver/polymeric NPs composed of Ag core and three different polymeric shells: polyvinyl alcohol (PVA), polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). Thereafter, the core/shell NPs were loaded with a chemotherapeutic agent doxorubicin (DOX). Finally, the cytotoxic effects of the different core-shell Ag/polymeric NPs-based combinatorial therapeutics were tested in-vitro against breast cancer (MCF-7) and human fibroblast (1BR hTERT) cell lines. AgNPs, Ag/PVA and Ag/PVP NPs were more cytotoxic to MCF-7 cells than normal fibroblasts, as well as DOX-Ag, DOX-Ag/PVA, DOX-Ag/PEG and DOX-Ag/PVP nanocarriers (NCs). Notably, low dosage of core-shell DOX-loaded Ag/polymeric nanocarriers (NCs) exhibited a synergic anticancer activity, with DOX-Ag/PVP being the most cytotoxic. We believe that the prepared NPs-based combinatorial therapy showed a significant enhanced cytotoxic effect against breast cancer cells. Future studies on NPs-based combinatorial therapy may aid in formulating a novel and more effective cancer therapeutics.