Red blood cells (RBCs) play a crucial role in delivering oxygen to tissues with their distinctive shape. However, the mechanisms underlying cellular deformation and rupture due to stress, which lead to diseases such as acute renal failure, pulmonary hypertension, anemia, and gallstone formation, remain poorly understood. Here, we investigate the mechanism of membrane protrusion and present a highly effective method to restore the morphology and function of damaged RBCs. We propose ultrasound-triggered nanodroplets loaded with oxygen and glucose to increase the local concentrations of these substances around RBCs and facilitate the rapid release of their payloads to repair fatigued RBCs under ultrasound. We identify a critical membrane protrusion length threshold of one-third the cell’s diameter, beyond which the skeleton structure fractures and prevents repair. Our findings demonstrate how nanodroplets can efficiently deliver oxygen and glucose to expose membrane connection and trigger cytoskeleton reorganization to repair cellular structure. In an in vitro extracorporeal membrane oxygenation (ECMO) model, our method reduces the percentage of abnormal RBCs to 5% and decreases free hemoglobin concentration by 50%. This work offers new insights into RBC rejuvenation and strongly supports the potential of ultrasound-triggered nanodroplets for revitalizing fatigued RBCs, contributing to long-term health and well-being.