[Objective] To investigate the clinical value of serum NFE2L2 in non-traumatic osteonecrosis of the femoral head. [Methods] This respective study analyzed clinical data of 79 NONFH patients and 80 healthy controls from August 2021 to February 2022, and compared serum NFE2L2 levels between two groups. Receiver operating characteristic analysis was performed to determine the diagnostic value of serum NFE2L2 in NONFH. [Results] Patients with NONFH displayed an increased serum NFE2L2 compared with controls (P<0.05). The levels of NFE2L2 were positively correlated with ARCO stage and VAS, and inversely correlated with Harris scores. ROC analyses showed that the AUC of NFE2L2 was 0.769. [Conclusion] Serum NFE2L2 levels were significantly correlated with disease severity of NONFH and may serve as a potential biomarker for NONFH.