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Dengue virus poses a serious worldwide health threat with up to 400 million infections occurring annually in over 100 countries. Currently, there are no specific therapeutics available, and the only licensed vaccine encompasses risk of hospitalization in immunologically naive individuals. In the current work for the first time we are reporting dengue virus type 2 (DENV2) inhibitory activity of newly designed 3-chlorobenzyl linked 1,9-diazaspiro[5.5]undecane derivatives. Compounds with substitutions featuring 2-methylbenzyl (SPO-6, EC50 = 11.43 ± 0.87 μM), 4-bromobenzyl (SPO-7, EC50 = 14.15 ± 0.50 µM), and 4-cyanobenzyl (SPO-13, EC50 = 20.77 ± 1.92 µM) groups and Ribavirin (IC50=50.9±18 µM, J. Gen. Virol.2006,87, 1947-1952) were found to be potent against DENV2 in a cell-based assay. Docking calculations identified NS5-methyltransferase as the most probable target for this series of compounds. Molecular dynamics simulations of NS5-methyltransferase reproduced the experimental binding affinity findings by yielding ΔGbind values that predicted SPO-6 to possess the most favorable binding energy of -27.2 ± 3.9 kcal/mol compared to SPO-7, SPO-13, and Ribavirin with -22.5 ± 4.7, -22.5 ± 4.6, and -20.0 ± 4.6 kcal/mol, respectively. In addition, based on Lipinski’s rule of 5 SPO-6 was found to be nontoxic and possessed a better score of drug likeness (5.87) in comparison to the standard drug ribavirin (1.72).