Despite the complexity of research, high cost and time constraint, dengue research is undergoing a vast transformation with remarkable findings, include investigating the potential of plant-based compounds. A research investigated the potential of two flavonoids (clitorin and manghaslin) detected in Carica papaya leaf juice against dengue virus serotype-2 was conducted. This research used in silico model (docking simulation) in exploring the interaction of the two flavonoids on functional activity of two non-structural proteins involving in dengue viral ribonucleic acid (RNA) replication, i.e. NS2B/NS3 protease (NS2B/NS3) and NS5-RNA-dependent RNA polymerase (NS5-RdRp). The same flavonoids were then tested on in vitro model (plaque assay) to assess their antiviral effect through number of plaque forming units per mL. The docking simulation revealed the two flavonoids potentially bind onto the two targeted dengue proteins that are important for dengue viral replication but clitorin is predicted to have stronger binding interaction with the NS5-RdRp while manghaslin is predicted to have stronger binding interaction with the NS2B/NS3 protease. Both flavonoids inhibited the plaque formation. Other than in vivo research, the findings from this study also propose clitorin and manghaslin as a potential inhibitor of NS5-RdRp and NS2B/NS3 protease, which could be further investigated to exploit their drug likeness properties such as adsorption, distribution, metabolism and excretion.