Aseptic loosening is a major complication of prosthetic joint surgery and is associated with impaired osteoblast homeostasis. Cortistatin (CST) is a neuropeptide that protects against inflammatory conditions. In this study, we found that expression of CST was diminished in patients with prosthetic joint loosening and in titanium (Ti) particle-induced animal models. A Ti particle-induced calvarial osteolysis model was established in wild-type and CST gene knockout mice; CST deficiency enhanced, while exogenously added CST attenuated, the severity of Ti particle-mediated osteolysis. CST protected against inflammation as well as apoptosis and maintained the osteogenic function of MC3T3-E1 osteoblasts upon stimulation with Ti particles. Furthermore, CST antagonized reactive oxygen species production and suppressed caspase-3-associated apoptosis mediated by Ti particles in osteoblasts. Additionally, CST protects against Ti particle-induced osteolysis through tumor necrosis factor receptor 1. Taken together, CST might provide a therapeutic strategy for wear debris-induced inflammatory osteolysis.