Silver nanoparticles have been widely applied for biomedical areas owing to their potent antiviral and antibacterial activities. Synthesis of silver nanoparticles using biomacromolecules is more efficient, environment-friendly, and cost-saving compared with the traditional approach. In this paper, a novel approach was developed to establish a reaction system with Ag⁺-BH4--sericin to synthesize silver nanoparticles conjugated to sericin (AgNPs-Sericin). Sericin could be as a good dispersant and stabilizing agent, which is able to modify nanoscaled AgNPs, the average diameter of which was only 3.78 ± 1.14nm prepared in a 0.3 mg/ml sericin solution. The characterizations of the AgNPs-Sericin were determined by FTIR, thermogravimetry, and XRD analyses. The results showed that the synthesized AgNPs conjugated with sericin as organic phase. Via SAED and XRD analysis, we showed that these AgNPs formed polycrystalline powder with a face-centered cubic structure of bulk metals. Moreover, we investigated the antiviral and antibacterial activities of AgNPs-Sericin, and the results showed that AgNPs-Sericin exhibited potent anti-HIV-1 activity against CCR5-tropic and CXCR4-tropic strains, but no significant cytotoxicity was found toward human genital epithelial cells compared with free silver ions, which are accepted as a commonly used potent antimicrobial agent. Moreover, its antibacterial activity was determined via flow cytometry. The results showed that AgNPs-Sericin could suppress gram-negative (E. coli) and grampositive (S. aureus) bacteria, but more was potent for the gram-negative one. We concluded that our AgNPs-Sericin could be a potential candidate as a microbicide or antimicrobial agent to prevent sexually transmitted infections.