Tumor Necrosis Factor-alpha (TNF-α), a multifunctional cytokine responsible for providing resistance against infections, inflammation, and cancers. TNF-α has emerged as a promising drug target against several autoimmune and inflammatory disorders. Several synthetic antibodies (Infliximab, Etanercept, and Adalimumab) are available, but their potential to cause severe side effects has prompted them to develop alternative small molecules-based therapies for inhibition of TNF-α. In the present study, combined in silico approaches based on pharmacophore modeling, virtual screening, molecular docking, and molecular dynamics studies were employed to understand significant direct interactions between TNF-α protein and small molecule inhibitors. Initially, four different small molecule libraries (∼17.5 million molecules) were virtually screened against the selected pharmacophore model. The identified hits were further subjected to molecular docking studies. The three potent lead compounds (