Angiogenesis contributes to heart functional recovery after acute myocardial infraction (AMI). We have previously reported that sublimation of vitamin B6 (VB6) prevents multiple cardiovascular diseases. Whether VB6 promotes angiogenesis to prevent cardiac dysfunction following AMI remains unknown. Angiogenesis was evaluated by measuring the number of tube formation in vitro and neovascularization by staining CD31 in vivo. Cardiac function was measured using echocardiography. VB6 upregulates cell migration and tubule formation in cultured human umbilical vein endothelial cells, accompanied with increased AMP-activated protein kinase (AMPK) alpha T172 phosphorylation and vascular endothelial growth factor A production. While, these effects are abolished by AMPK inhibitor compound C and ADaM-site activator 991. Mechanistically, VB6 allosterically activated AMPK by interacting with AMPKβ subunit, resulting in a stable conformation of AMPKαβγ complex with AMPKα-T172 phosphorylation. In vivo, long-term supplementation of VB6 significantly improves heart functions, increases neovascularization, and decreases cytokines in mice following AMI. In conclusion, VB6 promotes heart functional recovery through AMPK-mediated angiogenesis following AMI. In perspective, ischemic heart injury is limited by VB6.