The study aimed to explore the efficacy and potential mechanisms of a naturally aromatic cyanogenic compoundamygdalin (AMY) in treating glucocorticoid (GC)-associated necrosis of the femoral head (GANFH). We demonstrated that GC exacerbates the oxidative stress (OS) microenvironment via promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression in human, rat, and mesenchymal stem cells (MSCs) samples, thus generating excessive reactive oxygen species (ROS), leading to increased apoptosis and unbalanced osteolipogenic differentiation. Furthermore, computational docking results revealed that AMY could bind specifically to the predicted binding sites of NOX4. Additionally, AMY ameliorated the OS microenvironment of MSCs via decreasing NOX4 expression and inhibiting NOX4/ROS/p38MAPK signaling, thereby reversing the GC-induced apoptosis and imbalanced osteolipogenic differentiation, and ultimately alleviating GANFH. In summary, we demonstrated for the first time that AMY attenuated apoptosis and maintained osteolipogenic differentiation balance in MSCs via specifically targeting NOX4, inhibiting NOX4/ROS/p38MAPK signaling, thereby treating GANFH.