The current study highlights the effective role of silver nanoparticles in improving the tumor targeting efficiency of epirubicin, chemotherapeutic agent. Regarding this, poly (vinyl alcohol)-coated silver nanoparticles were designed in a particle size of 18 ± 0.1 nm. Furthermore, poly (vinyl alcohol)-coated silver nanoparticles were conjugated with epirubicin in a conjugation efficiency of 88 ± 2%. Moreover, both poly (vinyl alcohol)-coated silver nanoparticles and epirubicin-conjugated poly (vinyl alcohol)-coated silver nanoparticles were radio- iodinated using iodine-131 isotope and yielded 90.6 ± 0.1% and 80 ± 2%, respectively. Crucially, the comparative in-vivo distribution of radioiodinated poly (vinyl alcohol)-coated silver nanoparticles and epirubicin-conjugated poly (vinyl alcohol)-coated silver nanoparticles were studied in healthy and tumor models. Interestingly, the radioiodinated epirubicin-conjugated poly (vinyl alcohol)-coated silver nanoparticles exhibited reticuloendothelial system (RES) shirking and prolonged blood concentration. In addition, it targeted tumor site by 22.8 ± 1% ID/g within 1 h post IV injection. Further, the tumor targeting efficiency of the new systemwas confirmed by calculating the tumor to normal tissue and the tumor to blood ratios were 12.67 ± 0.5 and 1.74 ± 0.05, respectively at 1 h post IV injection. Consequently, the findings provided the radioiodinated epirubicin- conjugated poly (vinyl alcohol)-coated silver nanoparticles as a new potential approach for tumor targeting with a goal of treatment and/or imaging.