In-silico pipeline is applied for identifying and designing novel inhibitors against ZIKV NS1 protein. Comparative molecular docking studies are performed to explore the binding of structurally diverse compounds to ZIKV NS1 by AutoDock/Vina and GOLD. The Zika virus (ZIKV) is a flavivirus, responsible for life-threatening infections and transmitted by Aedes mosquitoes in other organisms. It is associated with Guillain Barre Syndrome (GBS) and microcephaly. This epidemic increase in GBS and microcephaly convoyed the World Health Organization to affirm ZIKV a public health crisis. To combat the ZIKV infections, non-structural protein 1 (NS1), a major host-interaction molecule contributing towards replication, pathogenesis and immune evasion is targeted in the current study. For this purpose, a comprehensive study is required to develop potential novel antiviral inhibitors. Three compounds were identified through docking programs exhibiting properties which are non-toxic to human host and could inhibit the elusive ZIKV. Significant interaction with active site residues and H-bond interactions with the key residues were analyzed for these compounds using molecular dynamics simulation. Free energy calculation predicted higher affinity of Deoxycalyxin-A for ZIKV NS1. This study contributes towards fighting ZIKV infections and can help researchers in designing drug for the treatment of ZIKV.