Dengue virus (DENV) disease, a life-threatening disease, is caused by DENV. In this research, a total of 24 analogues were designed by targeting the 2, hydroxyl and 2, methyl groups of parent fucoidan, and their interactions with DENV were investigated for their ability to suppress DENV through the use of docking, MM-GBSA, and Molecular dynamics (MD) simulation experiments. The Glide module was utilised in order to perform docking of ligands against DENV-2 (PDB ID: 1L9K). Additionally, the QikProp module was utilised for in-silico ADMET screening, Tox Pro-II was utilised for in-silico toxicity, and the Prime MM-GB/SA module was utilised for binding energy during the docking process. Compound FUC-4 has the highest G-score (- 9.58 kcal/mol) when compared to all the 24 derivatives and also standard S-adenosyl L-homocysteine (SAH), It is significantly active against DENV-2 NS5 methyltransferase when compared with standard. The residues Gly88, Glu111, Cys82, Gly81, Val132, Phe133, Val180, Thr104, and Asp131 of DENV-2 methyltransferase play a crucial role in binding with the selected ligand. The binding free energy revealed that the ligands FUC-4, FUC-6, and FUC-10 have significant Glide scores. These molecules may produce efficient anti-dengue activity against DENV2. Compound FUC-4 was subjected to MD simulation at 100 ns and it showed the highest binding affinity with methyl transferase. The results of In-silico anti-dengue studies on fucoidan derivatives revealed that the FUC-4, FUC-6, and FUC-10 showed good binding activity against DENV -MTase. The Benzoylated fucoidan (FUC-4) was identified as a potent fucoidan analogue and it was subjected to wet lab preparation followed by structural characterisation using UV, ATR-IR, 1HNMR, and Mass spectral studies. The synthesized FUC-4 was further screened for in-vitro antiviral assay for its anti-dengue activity and proved to be a potent anti-dengue hit molecule, which can be a future lead compound for DENV infections.