Background: Safflower extract and aceglutamide (SA) has been used clinically for the treatment of cerebrovascular diseases such as cerebral embolism, hemorrhage, and mental deterioration. This study aimed to investigate the effect and mechanism of SA injection in the recovery of peripheral innervations of diabetic mice. Methods: The C57BL/6 male mice were divided into four groups: normal control group (n = 44), diabetic group (n = 44), diabetic + SA group (diabetic mice treated with SA injection, n = 44), and diabetic + SA + vascular endothelial growth factor receptor (VEGFR)1-BL group (diabetic mice treated with SA injection and VEGFR 1 blocking antibody n = 24). The streptozotocin-induced diabetic mice model and injured peripheral nerve mice model were built. The mice with injured peripheral nerves were intraperitonealy administered with SA injection for successive 21 days. The ceal sensitivity, number of ceal nerve fibers, and contents of vascular endothelial growth factor (VEGF)-B and various neurotrophic factors such as nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) in ceal tissue of four groups were observed. Results: The diabetic group showed decreased number of ceal nerve fibers, compared with the control group (P = 0.002). And compared with the diabetic group, the diabetic + SA group showed a significant increase in the number of nerve fibers (P = 0.024) and the contents of VEGF-B,NGF,andGDNFinthecea(allP<0.05).However,whenthediabeticmiceweretreatedwiththeblockingantibodiesspecializedfor VEGF-B receptor, the neutralization ofVEGFR-1 completely abolished the increased expression of NGF and GDNF stimulated by SAinjection. Conclusions: SA injection could reduce the nerve injury caused by diabetic peripheral neuropathy, and its protective effect might be associated with the promotion of the expressions of VEGF-B, NGF, and GDNF.