Zika virus is an arthropod-borne virus that transmitted through various mosquito vectors and containing structural and non-structural proteins in their genome assembly. It is an emerging infectious disease causing very serious complications such as Microcephaly in infants and Guillain–Barré syndrome in adults. After analyzing the previous studies, we have targeted the NS2B-NS3 protease that serves as an effective drug target owing to its role in viral replication and immune evasion within the host. The main objective of the study is to find out the best compound(s) against ZIKA virus that can inhibit the transmission cycles as well as the replication process. We have subjected selected 20 Flavonoids from various Origanum species found in the Mediterranean regions and performed pharmacological analysis using SwissADME followed by the Molecular Docking studies using AutoDock Vina 4.0. The best hit compound after docking analysis were subjected to molecular dynamic simulation at 100 ns using Desmond Schrodinger to analyze the stability of molecule. After pharmacological analysis and molecular docking analysis, Isovitexin and Cirsiliol were observed to be best hit compound against NS2B-NS3 complex i.e. (-8.8 kcal/mol and -8.5 kcal/mol). Both the hit compounds were subjected to dynamic studies where they also exposed the better stability with the complex and inhibiting the replicating molecules observed through ligand-protein contacts. In the present study, we recommend both the hit compounds for in vitro and in vivo study for further investigation with respect to ZIKA virus.