Objective The aim of this study was to observe the morphological changes of the retina at early stage of diabetes in SD rat induced by multiple injections of low-dose (multi-low-dose) streptozotocin (STZ). Methods Seventy-five male SD rats were randomly divided into control (CON)(n=30) and diabetes mellitus (DM)(n=45) groups. Rats in the DM group received multiple low-dose STZ i.v. injection for 5 consecutive days (30 mg/kg). The blood glucose, body weight, and other parameters were observed once a week after injection. In the 4, 8 and 12 w, the morphological changes in the retina were observed using HE and immunohistochemical (IHC) staining, vasculature digest preparation and transmission electron microscopy (TEM). Results The body weight of animals in the DM group was decreased from 2 w. The average body weight of the DM group was significantly lower than that of CON group (P<0.01). The average blood glucose of DM group was significantly higher than that of the CON group (P<0.01). TEM examination revealed thickened capillary basement membrane and dilatation of capillary at 4 w. trypsin digest preparation showed endothelial cell hyperplasia, mitochondrial swelling, cristae disruption, and vacuolar degeneration in capillary endothelial cells at 8 w. Retina HE staining showed retinal capillary dilatation and interstitial edema, capillary intumescence, apoptosis in endothelial cells in the DM group at 12 w. The control group had no obvious abnormalities. Staining of GAFP in the retina indicated decreased expression in the ganglion cell layer and nerve fiber layer, bipolar cells and ganglion cells, mitochondrial swelling and cristae disruption in pericytes, decreased membranous disc, and widened gap between membranous discs at 12 w. Conclusions Our findings indicate that an early stage diabetic retinopathy (DR) can be induced in rats by multiple low-dose streptozotocin injection. This may serve as a valuable preclinical model for studying the pathogenesis, pharmacodynamics and potential therapies for DR and its complications.