The current global occurrence of dengue infection annually is approximately 400 million, with a case fatality rate of 2.5%. However, there are no antiviral agents. Carica papaya leaf extract is known for its medicinal value, due to the presence of organic compounds that possess antimicrobial, anti-inflammatory, and antioxidant activities. This study determined the anti-dengue effect of C. papaya leaf extract silver synthesized nanoparticles. In this study, aqueous and non-aqueous extractions were carried out, followed by the synthesis of silver nanoparticles as well as characterization through Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy. The in vitro anti-dengue effect was evaluated using a focus reduction neutralization test on kidney Vero E2 cell lines. In silico studies involved molecular docking to determine the potential interactions between the bioactive compounds in C. papaya leaf extract and the viral NS5 protein. C. papaya leaf methanol extract silver synthesized nanoparticle was the most promising with an IC50 of 9.20 µg/mL. Molecular docking showed 5,7 dimethoxycoumarin as the best ligand, with binding energy of −7.75 kcal/mol, indicating high affinity for the NS5 protein. These results highlight that C. papaya leaf methanol extract silver synthesized nanoparticles could be used to inhibit dengue virus type 2 viral replication. However, we recommend further studies to determine their toxicity and the safety profiles.