Tumor necrosis factor α (TNF-α) is an important therapeutic target for rheumatoid arthritis, inflammatory bowel disease, and septic hepatitis. In this study, structure-based virtual ligand screening combined with in vitro and in vivo assays were applied. A lead compound, benpyrine, could directly bind to TNF-α and block TNF-α-trigged signaling activation. Furthermore, the endotoxemic murine model showed that benpyrine could attenuate TNF-α-induced inflammation, thereby reducing liver and lung injury. Meanwhile, administration of benpyrine by gavage significantly relieved the symptoms of collagen-induced arthritis and imiquimod-induced psoriasiform inflammation in mice. Thus, our study discovered a novel, highly specific, and orally active small-molecule TNF-α inhibitor that is potentially useful for treating TNF-α-mediated inflammatory and autoimmune disease.