This chapter describes chronic pancreatitis (CP)-induced alterations in the levels of key players of antioxidative defense system and associated factors. It also discusses the role of antioxidants such as selenium, allopurinol, β-carotene, N-acetylcysteine (NAC), and pentoxifylline as well as some phytochemicals in amelioration of oxidative stress-mediated severity of pancreatic disease in CP patients. CP is known to generate free radicals and to produce oxidative stress in patients. Alcohol consumption is one of the major environmental factors that significantly influences the clinical condition of CP. Establishment of redox balance is highly complicated, requiring sophisticated regulation of scavenger bioavailability and of reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. The phytochemicals such as rottlerin, ellagic acid, embelin, lycopene, curcumin, isothiocyanates, capsaicin, green tea, and resveratrol have been shown to act to both attenuate the production of ROS in CP and afford prevention of the disease.