Osteomyelitis (OM) is a severe inflammatory bone disease primarily caused by Staphylococcus aureus (S. aureus), characterized by excessive inflammation, oxidative stress, and osteoblast dysfunction. Activation of extrinsic apoptotic signaling, particularly the TRAIL–TNFR1–caspase axis, contributes to bacteria-induced osteoblast death; however, effective therapeutic strategies targeting this pathway remain limited. MJ411, a natural isocoumarin derivative, possesses anti-inflammatory and antioxidant properties, suggesting its potential in infection-associated bone disorders. In this study, we investigated the protective effects of MJ411 in bacterial component–induced OM models. In vitro, MJ411 significantly suppressed lipopolysaccharide (LPS)- and S. aureus protein A (SpA)-induced inflammatory cytokine and chemokine expression in MC3T3-E1 osteoblasts. MJ411 reduced reactive oxygen species (ROS) generation, restored antioxidant enzyme expression, and attenuated apoptosis by inhibiting TRAIL, TNFR1, and caspase-8 activation. Furthermore, MJ411 rescued inflammation-impaired osteogenic differentiation, as evidenced by increased ALP activity, mineralization, and osteogenic marker expression. Collectively, these findings demonstrate that MJ411 protects against bacteria-associated osteoblast dysfunction by regulating inflammation, oxidative stress, and TRAIL–TNFR1–mediated apoptotic signaling, highlighting its therapeutic potential for infection-related bone diseases.