Dengue fever remains as a serious infectious disease that can have horrible consequences, including death. Although it is not a new disease, there is no effective antiviral drug available to treat this disease. In this study, fragment-based drug design and molecular docking approach have been done to generate the potential drug candidates for inhibiting β-OG pocket binder of the envelope protein responsible for mediating DENV entry into the host cell. About 190,084 natural product compounds were obtained from ZINC15 database. The rules of three and pharmacological test were employed against the natural product compounds, resulting 1,610 favorable fragments. These fragments were docked into the polar and nonpolar regions of β-OG pocket binder cavity, respectively. The potential fragments, which bound to each region, were linked to generate 6,487 ligands. The rules of five and pharmacological test against the ligands have been done to discard the ligands with the undesired molecular properties. The inhibition activity of 2,950 ligands was evaluated by employing rigid and flexible molecular docking simulation. AX1312, AZ0830, and AZ0492 show a promising potential as the drug leading candidate for treating dengue fever as they have a better binding free energy and molecular interaction with DENV envelope protein compared to the standard compound, n-octyl-β-D-glucoside. Further in vitro and in vivo analysis are required to validate their inhibition activity against DENV envelope protein under actual biological condition.