NADPH oxidases (NOX) are major players in generating reactive oxygen species (ROS), implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of NOX4 inhibitor (GLX7013114), in two in vivo experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Diabetic-treated animals received GLX7013114 topically (20μl/eye, 10mg/ml, once daily), for 14d (Paradigm A/preventive) and 7d (Paradigm B/treated), 48hr and four wks post STZinjection, respectively. A number of methodologies were employed (immunohistochemistry, western blot, real time PCR, ELISA, PERG) to assess the diabetes induced early events of DR, namely oxidative stress, neurodegeneration and neuroinflammation, and the effect of GLX7013114 on the diabetic insults. GLX7013114, administered as eye-drops (paradigms A,B) was beneficial in treating the oxidative nitrative stress, activation of caspase-3 and micro/macroglia and attenuation of neuronal markers. It also attenuated the diabetes induced increase in VEGF, Evans-Blue leakage and proinflammatory cytokine levels (TNF-α protein, IL-1β/IL-6 mRNA). PERG amplitude values suggested that GLX7013114 protected retinal ganglion cell (RGC) function (Paradigm B). In conclusion, this study provides new findings regarding the pharmacological profile of the novel NOX4 inhibitor GLX7013114, as a promising therapeutic candidate, for the treatment of the early stage of DR.