Various clinical symptoms are caused by dengue virus ranging from mild fever to severe hemorrhagic fever while there is no successful anti-dengue therapeutics available. Among different strategies towards identifying and developing anti-dengue therapeutics, testing anti-dengue properties of known drugs could represent an efficient strategy for which information of its medical approval, toxicity and side effects is readily available. In this study, we evaluated the antiviral activity of some medical compounds towards dengue NS2B-NS3 protease (DENV2 NS2B-NS3pro) as a target to inhibit dengue virus replication. Mefenamic acid, a non-steroid anti inflammatory drug and doxycycline, a derivative antibiotic of tetracycline both showed significant inhibition potential against DENV2 NS2B-NS3pro Ki values 32 ± 2 μM and 55 ± 5 μM respectively. The effective cytotoxic concentrations of 50% (CC50) against Vero cells were evaluated for mefenamic acid (150 ± 5 μM) and doxycycline (125 ± 4 μM). Concentrations lower than CC50 were used to test the inhibition potential of these compounds against DENV2 replication in Vero cells. The results showed significant reduction in viral load after applying mefenamic acid and doxycyline in concentration dependent manner. Mefenamic acid reduced viral RNA at EC50 of 32 ± 4 μM whilst doxycycline EC50 was 40 ± 3 μM. Mefenamic acid showed higher selectivity against dengue virus replication in vitro compared to doxycycline. These findings underline the need for further experimental and clinical studies on these drugs utilizing its anti-dengue and anti-inflammatory activities to attenuate the clinical symptoms of dengue infection.