Antimicrobial resistance poses a significant threat to public health and social development worldwide. This study aimed to investigate the effectiveness of silver nanoparticles (AgNPs) in treating multidrug-resistant bacterial infections. Eco-friendly spherical AgNPs were synthesized using rutin at room temperature. The biocompatibility of both polyvinyl pyrrolidone (PVP) and mouse serum (MS)-stabilized AgNPs was evaluated at 20 μg/mL and showed a similar distribution in mice. However, only MS-AgNPs significantly protected mice from sepsis caused by the multidrug-resistantEscherichia coli (E. coli)CQ10 strain (p= 0.039). The data revealed that MS-AgNPs facilitated the elimination ofEscherichia coli (E. coli)in the blood and the spleen, and the mice experienced only a mild inflammatory response, as interleukin-6, tumor necrosis factor-α, chemokine KC, and C-reactive protein levels were significantly lower than those in the control group. The results suggest that the plasma protein corona strengthens the antibacterial effect of AgNPsin vivoand may be a potential strategy for combating antimicrobial resistance.