Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness among individuals with diabetes mellitus. Current clinical diagnostic criteria mainly base on visible vascular structure changes, which are insufficient to identify diabetic patients without clinical DR (NDR) but with dysfunctional retinopathy. This review focuses on retinal endothelial cells (RECs), the first cells to sense and respond to elevated blood glucose. As blood glucose rises, RECs undergo compensatory and transitional phases, and the correspondingly altered molecules are likely to become biomarkers and targets for early prediction and treatment of NDR with dysfunctional retinopathy. This article elaborated the possible pathophysiological processes focusing on RECs and summarized recently published and reliable biomarkers for early screening and emerging intervention strategies for NDR patients with dysfunctional retinopathy. Additionally, references for clinical medication selection and lifestyle recommendations for this population are provided. This review aims to deepen the understanding of REC biology and NDR pathophysiology, emphasizes the importance of early detection and intervention, and points out future directions to improve the diagnosis and treatment of NDR with dysfunctional retinopathy and to reduce the occurrence of DR.