This chapter focuses on the role of antioxidant vitamins in protecting the gastrointestinal (GI) tract from oxidative stress. A systems medicine approach is used since it alone is sufficiently comprehensive to capture the broad range of relevant complexities and interrelationships relevant to GI protection. Systems medicine utilizes and integrates the vast amount of information gained from genomics and metagenomics, as well as environmental factors, and applies this information to better patient care. A major goal of system medicine is to develop paradigms to treat or slow the progression of chronic diseases, that is, disease prevention. GI disorders are quintessential examples of chronic inflammation with its attendant oxidative stress. Genomics and metagenomics have provided great insight into the underlying molecular mechanisms for GI disorders and will eventually help define individualized diets to minimize chronic inflammation. While the role of antioxidant nutrients and micronutrients is promising, there is a need for large-scale well-designed clinical trials supported by studies using animal models.