Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. A critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies are in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high throughput structure-based computational screening using ensemble docking for small molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scored ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with second-highest calculated binding affinity showed experimentally ∼84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 -5 molar concentration. This finding may pave the way for designing small molecule inhibitors of hIL-6 of therapeutic significance.