In this study, rice plants were co-exposed to selenium (Se) and silica (Si) under arsenic (As) stress to evaluate As accumulation in rice grains, associated cancer risk, and its impact on the types and numbers of grain metabolites. A total of 58 metabolites were identified, of which, 19 belong to sugars, and drastically altered during different treatments. Arsenic exposure significantly reduced monosaccharides, i.e., D-glucose (83%) >D-galactose (60%) >D-fructose (57%) >D-ribose (29%) but increased that monosaccharide units which have antioxidant properties (i.e. alpha-D-glucopyranoside and melibiose). However, the levels of D-galactose, fructose, and ribose were significantly increased during co-supplementation of selenite (Se-IV) and Si under As stress. Other groups of rice grain metabolites, like sugar alcohols, organic acids, polyphenols, carboxylic acids, fatty acids, and phytosterols, were also significantly altered by As exposure and increased in grains of Se-IV and Si supplemented rice compared to alone As exposure. In brief, rice growing in As-affected areas may have a low level of different metabolites. However, supplementation by selenite (Se-IV) with Si not only increased metabolites and amylose/amylopectin ratio but also reduced similar to 90% of As accumulation in grains. Thus, the use of Se-IV with Si might be advantageous for the locals to provide a healthy diet of rice and limit As-induced cancer risk up to 10-fold.