Dengue virus (DENV) remains a major global health threat, particularly in tropical and subtropical regions, due to the lack of effective antiviral therapies. In this study, we evaluated a novel combination strategy using melittin, a bee venom-derived antiviral peptide, together with Clinacanthus nutans extract to enhance antiviral efficacy while reducing melittin-associated cytotoxicity against dengue virus serotype 2 (DENV-2). Cytotoxicity was assessed in Vero cells using a cell viability assay, whereas antiviral activity was evaluated by focus-forming unit (FFU) reduction assay, cell-based ELISA, FFU titration assay, and immunofluorescence assay (IFA). Melittin (1.25–2.5 µg/mL) and C. nutans extract (15.625–500 µg/mL) maintained cell viability above 80%, whereas 5 µg/mL melittin markedly reduced cell viability. Notably, co-treatment with C. nutans restored cell viability to above 80%, demonstrating a significant cytoprotective effect. More importantly, the combination treatment exhibited greater antiviral activity than either agent alone, resulting in complete inhibition of viral infection at lower concentrations while simultaneously suppressing intracellular viral protein expression and production of progeny viruses. These findings suggest that C. nutans may enhance the antiviral activity of melittin while reducing its cytotoxicity under the conditions tested. Overall, this study provides preliminary evidence supporting the potential of this natural compound-based combination strategy and warrants further preclinical investigation as a candidate antiviral approach against DENV infection.