This study investigated the antiviral potential of silver nanoparticles (AgNPs) synthesized from Senna italica and Vepris reflexa plant extracts, rich in saponins and flavonoids. The aim was to explore the synthesis of AgNPs through green chemistry, followed by assessing their inhibitory activity against SARS-CoV-2 papain-like protease (PLpro) and evaluating cytotoxicity. The synthesized AgNPs were predominantly spherical in shape, with an average particle size in the nanoscale range (12–55 nm), as conformed by the transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses. A dose-dependent inhibition of SARS-CoV-2 PLpro was observed, with IC₅₀ values ranging from 0.12 to 0.48 mg/mL for different formulations. Cytotoxicity tests on Vero-76 cells revealed a high viability (>75%) at concentrations below 0.5 mg/mL for all AgNP samples. The findings suggest that the plant-derived AgNPs exhibit significant antiviral activity and minimal cytotoxicity, supporting their potential for further development as therapeutic agents.