Dengue is one of the most prevalent viruses transmitted by the Aedes aegypti mosquitoes. Currently, no specific medication is available to treat dengue diseases. The NS2B-NS3 protease is vital during post-translational processing, which is a key target in this study. Due to methoxy group substitution, methoxyflavones are more bioavailable and metabolically stable than hydroxylated flavones. To date, research on the anti-dengue activity of methoxyflavones is limited. Hence, this work aims to determine the inhibitory activity of methoxyflavones against the dengue NS2B-NS3. Methoxyflavones derivatives were screened using molecular docking. The result showed a strong binding interaction of compound 1 and compound 2 with NS2B-NS3 protease. Both compounds exhibited comparable binding energy as the reference compound, quercetin, with values lower than - 8.1 kcal/mol. Molecular dynamics simulation using GROMACS revealed the stability and stiffness of the complexes over a 100 ns time scale. In addition, an in vitro assay for NS2B-NS3 protease inhibition revealed inhibitory effects of compounds 1 and 2 with IC50 values of 316.80 µM and 463.30 µM, respectively. The ADMET analyses showed favorable pharmacokinetics profiles that comply with Lipinski's Rule of Five. Collectively, our findings suggest that compounds 1 and 2 inhibit dengue NS2B-NS3 activity. These findings hold promise of methoxyflavones as starting compounds for potential dengue treatment, highlighting the need for further investigation.