Background: Clozapine (CLZ) has been considered the mainstay drug in treatment of resistant schizophrenia. Diabetes mellitus has befallen during clozapine therapy. L-carnitine (LC) has protective effects against many health hazards. Aim of the work: This experiment aimed to examine the molecular mechanisms of pancreatic insult caused by CLZ in rats and the possible ameliorating effect of LC against that toxicity. Material and Methods: Thirty-five adult male albino rats were allocated into five groups equally: control groups (negative and vehicle), LC-treated group received 350 mg/kg/day LC, CLZ-treated group gavaged 25 mg/kg/day CLZ and the combined group gavaged LC+CLZ in the same previous doses. All treatments were given orally for 4 weeks. Results: CLZ-treatment triggered a significant rise in the mean values of body weight (BW) and serum of fasting blood glucose (FBG), amylase, insulin, Triglyceride Glucose (TyG) Index and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Also, a significant upsurge in lipid peroxidation and pro-inflammatory (Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-kB)) accompanying by a significant decrease of catalase (CAT), Hemo oxygenase-1 (HO-1) enzyme and nuclear factor erytheroid 2-related factor (Nrf2) activities and anti-inflammatory (IL-10), and decreased expression of Peroxisome proliferator activated receptor alfa (PPAR-α) in pancreatic tissues has occurred. There was histological and immunohistochemical evidence of pancreatic tissue injury with increased collagen fibers. The previous abnormalities were reversed when LC was given in the combined group. Conclusion: LC can ameliorate the pancreatic oxidant, inflammatory, and apoptotic impacts induced by CLZ.