The lack of effective conventional therapies against dengue has created an interest in herbal preparations as alternative therapies. In the present study, in vitroeffects of Cordia curassavicaessential oil (EO) on both dengue virus replication and cytokine production were examined. Predictions ofmolecular interactions between EO compounds and virus and cell proteins were performed with AutoDock Vina. The EO inhibited replication of dengue virus serotypes at IC50< 30 μg/mL, and it reduced 87% TNF-α, 67% IL-8 and 46% IFN-α in LPS-stimulated PBMCs.The main EO compounds were trans-β-caryophyllene (21.4%), germacrene D (17.8%), α-copaene (16.5%), trans-β-guaiene (8.2%), and α-pinene (6.0%). The first two compounds, δ-cadinene, α-muurolene, α-cubebene and β-burbonene were coupled to proteins involved in the TLR-4 cytokine effector pathway. 3,7-Guaiadiene was coupled to the viral E and C proteins. This study demonstrates the potential of C. curassavicaEO as a starting point for discovering novel therapeutic for dengue.