Dengue virus (DENV) has emerged as one of the most prevalent viruses in sub-tropical countries, yet there is no commercial drug available to combat DENV infection effectively. The RNA-capping and replication processes of DENV are regulated by NS5 methyltransferase (MTase). Hence, NS5 MTase is believed as a promising drug target for DENV. In this research, the DENV NS5 MTase was subjected to 6,842 Northern African Natural Product Database (NANPDB) compounds through computational simulation methods. Three crystal structures of DENV NS5 MTase, which contained S-adenosylhomocysteine (PDB ID: 4V0Q), S-adenosylmethionine (PDB ID: 3P97), and sinefungin (PDB ID: 4R8S), were used as the core template of the pharmacophore mapping in the SAH-binding site of DENV NS5 MTase. Four amino acid residues (Glu111, Asp131, Val132, and Asp146) were found to strongly interacted with SAH, SAM, and SFG, indicating that these residues may hold a vital role on the catalytic activity of DENV NS5 MTase. From the docking simulations, three ligands showed favorable inhibition activities by having lower ΔGbinding value than the standard ligands. Rutin has the lowest ΔGbinding value at -12.3586 kcal/mol, followed by isorhamnetin 3-rutinoside (-12.3203 kcal/mol), and tetra-o-galloyl glucose (-12.2039 kcal/mol). Pharmacological properties of these ligands were analyzed; no potential harmful effect was detected. Therefore, these ligands can be suggested as drug candidates for treating DENV infection by targeting SAH-binding site of NS5 MTase. The ligands efficacy needs to be validated through a series of in vitro, in vivo and clinical studies.