Diabetic corneal neuropathy (DCN) is a common complication of diabetes mellitus (DM). However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-alpha (PPAR)-α agonist, fenofibrate, on thirty patients (60 eyes) with type II DM. On in-vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, evidenced by the significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cells morphology also significantly improved in its cell circularity. Upon clinical examination, fenofibrate significantly improved patients’ neuropathic ocular surface status by increasing tear break-up time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with the improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signalling pathway, linolenic acid, cholesterol and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN.