Background <p>Obstructive sleep apnea (OSA) is a common sleep disorder characterized by the weakening or even termination of respiratory airflow during sleep. Patients with OSA have different degrees of damage to organs such as the brain, heart, liver, spleen, and intestines, with obvious metabolic disorders and inflammatory reactions.</p> Objective <p>This study was designed to investigate the mechanism of G protein-coupled receptor 1 (GPR1) in chronic intermittent hypoxia (CIH)-induced neuroinflammation in a mouse model of obstructive sleep apnea (OSA).</p> Results <p>CIH activated ferroptosis in BV-2 cells and mouse hippocampal neurons. GPR1 level was decreased in CIH mouse model and BV-2 cell model. Upregulating GPR1 alleviated cognitive dysfunction, neuroinflammatory injury, and ferroptosis in CIH mice. Upregulating GPR1 attenuated BV-2 cell activation, inflammatory response, and ferroptosis. TAFA1 bound to GPR1 and regulated ferroptosis in CIH. Reducing TAFA1 mitigated the improvement of GPR1 upregulation on CIH mice or BV-2 cells.</p> Conclusion <p>GPR1 effectively controls ferroptosis and attenuates the resulting neuroinflammation and injury in the context of OSA by regulating TAFA1.</p>