Background: Angiogenesis plays a crucial role in early wound healing by providing essential nutrients and oxygen to tissue cells, supporting the growth of epithelial and other tissue cells. The essence of angiogenesis lies in the proliferation and migration of endothelial cells. Pilose antler extract (PAE) accelerates early-stage wound healing. Proteomic analysis shows its role in vascular tension regulation, cell migration, and angiogenesis. Objective: This study aims to investigate the effects and pharmacological mechanisms of PAE on angiogenesis and vascular maturation during early wound healing. Methods: We used a full-thickness skin excision model in rats, utilizing endothelial cell analysis to examine PAE’s regulatory mechanisms on angiogenesis. Results: PAE accelerates vascular network formation and blood flow restoration in early wound healing. It promotes proliferation, migration, and formation of endothelial tubular structures by activating the PI3K-AKT pathway, upregulating VEGFR2 and p-AKT1 in endothelial cells. PAE also regulates Ang-1, Ang-2, and Tek expression, demonstrating time-dependent effects on angiogenesis and remodeling during healing. The positive effects of PAE on wound healing and blood flow recovery are counteracted when LY294002 inhibits PI3K activity. Conclusion: Local treatment with PAE increases VEGFR2 expression and activates the PI3K-AKT pathway to promote angiogenesis and accelerate wound healing while regulating Ang-1, Ang-2, and Tek expression, accelerating vascular maturation, and promoting functional vessel formation. Our study first reveals that PAE promotes angiogenesis by activating the PI3K-AKT pathway. Additionally, we monitored PAE’s time-dependent regulation of angiogenesis and remodeling, highlighting its role in maintaining balance.