Crop yield stability requires an attenuation of the reduction of yield losses caused by environmental stresses such as drought. Using a combination of metabolomics and high-throughput colorimetric assays, we analysed central metabolism and oxidative stress status in the flag leaf of 292 indica rice (Oryza sativa) accessions. Plants were grown in the field and were, at the reproductive stage, exposed to either well-watered or drought conditions to identify the metabolic processes associated with drought-induced grain yield loss. Photorespiration, protein degradation, and nitrogen recycling were the main processes involved in the drought-induced leaf metabolic reprogramming. Molecular markers of drought tolerance and sensitivity in terms of grain yield were identified using a multivariate model based on the values of the metabolites and enzyme activities across the population. The model highlights the central role of the ascorbate-glutathione cycle, particularly dehydroascorbate reductase, in minimizing drought-induced grain yield loss. In contrast, malondialdehyde was an accurate biomarker for grain yield loss, suggesting that drought-induced lipid peroxidation is the major constraint under these conditions. These findings highlight new breeding targets for improved rice grain yield stability under drought.