Piceatannol (PCN), a SIRT1 activator, regulates multiple oxidative stress mechanism and has anti-inflammatory potential in various inflammatory conditions. However, its role in Diabetic insulted peripheral neuropathy (DN) remains unknown. Oxidative stress and mitochondrial dysfunction are major contributing factors to DN. Myriad studies have proven that sirtuin1 (SIRT1) stimulation convalesce nerve functions by activating mitochondrial functions like mitochondrial biogenesis and mitophagy. Diabetic neuropathy (DN) was provoked by injecting streptozotocin (STZ) at a dose of 55 mg/kg, i.p to male Sprague Dawley (SD) rats. Mechanical, thermal hyperalgesia was evaluated by using water immersion, Vonfrey Aesthesiometer, and Randall Sellito Calipers. Motor, sensory nerve conduction velocity was measured using Power Lab 4sp system whereas The Laser Doppler system was used to evaluate nerve blood flow. To induce hyperglycemia for the in vitro investigations, high glucose (HG) (30 mM) conditions were applied to Neuro2a cells. At doses of 5 and 10 µM, PCN was examined for its role in SIRT1 and Nrf2 activation. HG-induced N2A cells, reactive oxygen exposure, mitochondrial superoxides and mitochondrial membrane potentials were restored by PCN exposure, and their neurite outgrowth was enhanced. Peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis was induced by increased SIRT1 activation by piceatannol. SIRT1 activation also enhanced Nrf2-mediated antioxidant signalling. Our study results inferred that PCN administration can counteract the decline in mitochondrial function and antioxidant activity in diabetic rats and HG-exposed N2A cells by increasing the SIRT1 and Nrf2 activities.