Hyperbaric oxygen therapy (HBO) shows promise as a treatment for peripheral artery disease (PAD), particularly when complicated by metabolic syndrome and diabetes. However, its precise effects on endothelial function remain unclear. This study explored the impact of HBO on angiogenesis and apoptosis in high-fat diet (HFD)-fed mice with limb ischemia, focusing on the role of sirtuin 1 (SIRT1). After 8 weeks on a chow or HFD, mice underwent unilateral femoral artery ligation and received HBO (3 ATA, 1 hour/day for 5 days). HBO improved blood flow, enhanced vascular density, and reduced apoptosis in ischemic calf muscles of HFD-fed mice. In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to high-glucose and oxygen-glucose deprivation (OGD) conditions, with or without HBO. HBO restored cell proliferation, migration, and tube formation under these conditions, reduced mitochondrial dysfunction, and decreased reactive oxygen species (ROS) production. However, these benefits were reversed by treatment with sirtinol, a SIRT1 inhibitor. HBO also increased SIRT1 expression and shifted mitochondrial dynamics toward fusion. Additionally, HBO upregulated angiogenesis-related proteins (VEGF, VEGFR, and SIRT1) while downregulating apoptosis-associated proteins (Bax, caspase-3, and p53). Collectively, these findings suggest that HBO enhances angiogenesis and reduces apoptosis in both in vivo and in vitro ischemia models, primarily through SIRT1 activation.