Large scale skin defects and skin reconstruction require the use of random skin flaps, and the size and shape of the flaps can be designed according to the wound. However, distal ischemic necrosis of random skin flaps is a major challenge after transplantation. The purpose of this study is to investigate the role of Genkwanin (GE) in ischemic necrosis of random skin flaps. Network pharmacology predicted the potential target SIRT1 and related pathways (including AMPK/TSC2 pathway) of GE. Transcriptomic sequencing further elucidated the mechanism of GE action. On postoperative day 7, skin flap survival was grossly evaluated, and laser Doppler imaging, Western blot analysis, histochemistry, and immunofluorescence all confirmed that GE enhanced autophagic flux. Moreover, autophagic flux exerted antioxidant, anti-apoptotic, and pro-angiogenic effects, ultimately increasing the flap survival rate. Even in the presence of H2O2, transwell, tube formation assays and other in vitro experiments such as cell fluorescence have shown that GE can still promote angiogenesis in HUVECs, accelerate cell proliferation rate, and reduce oxidative stress levels. Findings reveal GE enhances flap survival via SIRT1/AMPK/TSC2/mTOR -mediated enhancement of autophagic flux, offering a novel therapeutic strategy for ischemic tissue repair.