Environmental stress leads to the production of reactive oxygen species (ROS) and consequently oxidative stress, which limits plant productivity. Thus, new crop cultivars that are able to overcome oxidative stress are required to address the global issues of environmental, food, and energy security. Sweetpotato (Ipomoea batatas [L.] Lam) is considered an emerging multifunctional crop because of its high carbohydrate content and adaptation to marginal lands. Moreover, sweetpotato offers several health benefits for the aging population, as it is rich in low-molecular-weight antioxidants (LMWAs) (e.g., carotenoids, ascorbate, tocopherols, and polyphenols), dietary fiber, potassium, and minerals. We speculate that metabolic engineering of LMWAs in sweetpotato will lead to the development of smart cultivars with enhanced levels of antioxidants and abiotic stress tolerance. This review describes the current status of metabolic engineering of LMWAs in sweetpotato and the potential of sweetpotato in ensuring food and nutrition security in the twenty-first century. Here, we focus on carotenoids, ascorbate, tocopherols, and polyphenols including anthocyanins in transgenic sweetpotato plants. Additionally, we discuss the potential role of the sweetpotato Orange (IbOr) gene, involved in carotenoid accumulation and stress tolerance, in improving crop productivity under the changing global climate and alleviating the problem of vitamin A deficiency. Genetic engineering of the biosynthetic and metabolic genes of LMWAs in sweetpotato is currently under investigation via molecular breeding. We predict that metabolic engineering of antioxidants in sweetpotato will lead to the development of new cultivars with enhanced nutritional value and abiotic stress tolerance, which will ensure global food and nutrition security in the face of climate change.