BACKGROUND Due to its widespread prevalence, migraine is a common neurovascular condition that has a major impact on people's health and quality of life. Rutaecarpine (RUT) is one of the main effective components of Evodia rutaecarpa, which has a wide range of biological activities. However, the exact mechanism by which RUT improves migraine remain unknown. OBJECTIVE The purpose of this study was to investigate whether RUT improves migraine by inhibiting oxidative stress via activating the Nrf2 antioxidant system through the PTEN/PGK1 signaling pathway. METHODS In vivo, a mouse model of chronic migraine (CM) was established by repeated intraperitoneal injection of nitroglycerin (NTG). After treatment with RUT and Sumatriptan, behavioral tests were performed, followed by measurements of oxidative stress-related indicators in the trigeminal nucleus caudalis, expression of proteins associated with the Nrf2 antioxidant system, and the PTEN/PGK1 pathway. In vitro, PC12 cells were stimulated by 100 μM H2O2 for 24 h to induce oxidative stress, which was then treated with RUT. Furthermore, the role of PTEN in antioxidant stress of RUT was elucidated by knockout of the PTEN gene. RESULTS The results showed that RUT treatment improved NTG-induced migraine in mice by inhibiting oxidative stress. Importantly, RUT inhibited oxidative stress in NTG-induced mice or H2O2-induced PC12 cells via activating the Nrf2 antioxidant system by inhibiting PGK1 activity through PTEN. These results provide evidence that RUT improves migraine by activation of the Nrf2 antioxidant system through the PTEN/PGK1 pathway and provide new insights into the potential use of RUT as an effective drug development candidate for migraine.