The activity of glucagon-like peptide 1 (GLP-1R) is essential for preventing restenosis following vascular injury; however, the mechanism of dysfunctional GLP-1R glycosylation and ways to enhance the activity of GLP-1R on vascular surfaces in diabetic patients are poorly understood. In the present study, we investigated the N-glycosylation level and role of stress-associated endoplasmic reticulum protein 1 (SERP1) in preventing restenosis following carotid injury in diabetic rats. Our results showed that N-glycosylation levels in both rat aortic endothelial cells (RAOECs) and rat vascular smooth muscle cells (VSMCs) decreased gradually following glucose treatment in a concentration dependant manner. Furthermore, co-immunoprecipitation (Co-IP) analyses indicated that SERP1 could interact with GLP-1R in RAOECs and VSMCs. Moreover, SERP1 enhanced GLP-1R N-glycosylation and increased the production of phosphorylated endothelial nitric oxide synthase (eNOS) as well as proliferation of RAOECs. SERP1 also increased phosphorylated adenosine monophosphate activated protein kinase (AMPK) and decreased the migration of VSMCs. Importantly, intima media thickness (IMT) and neointimal hyperplasia were alleviated in the carotid artery of diabetic rats injected with SERP1 following balloon injury. We also found an increase in re-endothelialization and a decrease in VSMC proliferation in the carotid artery of diabetic rats injected with SERP1. In summary, the remarkable effects of SERP1 on reducing restenosis following vascular injury may contribute to future advancements in the treatment of diabetic vascular complications.