Patients with peripheral artery disease (PAD) and diabetes compose a high-risk population for development of critical limb ischemia (CLI) and amputation, although the underlying mechanisms remain poorly understood. Comparison of dysregulated microRNAs from diabetic patients with PAD and diabetic mice with limb ischemia revealed the conserved microRNA,miR–130b-3p. In vitro angiogenic assays demonstrated thatmiR-130brapidly promoted proliferation, migration, and sprouting in endothelial cells (ECs), whereasmiR-130binhibition exerted antiangiogenic effects. Local delivery ofmiR-130bmimics into ischemic muscles of diabetic mice (db/db) following femoral artery ligation (FAL) promoted revascularization by increasing angiogenesis and markedly improved limb necrosis and amputation. RNA-Seq and gene set enrichment analysis frommiR-130b–overexpressing ECs revealed the BMP/TGF-β signaling pathway as one of the top dysregulated pathways. Accordingly, overlapping downregulated transcripts from RNA-Seq and miRNA prediction algorithms identified thatmiR-130bdirectly targeted and repressed the TGF-β superfamily member inhibin-β-A (INHBA). miR-130b overexpression or siRNA-mediated knockdown of INHBA induced IL-8 expression, a potent angiogenic chemokine. Lastly, ectopic delivery of silencer RNAs (siRNA) targetingInhbaindb/dbischemic muscles following FAL improved revascularization and limb necrosis, recapitulating the phenotype ofmiR-130bdelivery. Taken together, amiR-130b/INHBAsignaling axis may provide therapeutic targets for patients with PAD and diabetes at risk of developing CLI.