Cassava is a staple crop that acclimatizes well to dry weather and limited water availability. The drought response mechanism of quick stomatal closure observed in cassava has no explicit link to the metabolism connecting its physiological response and yield. Here, a genome-scale metabolic model of cassava photosynthetic leaves (leaf-MeCBM) was constructed to study on the metabolic response to drought and stomatal closure. As demonstrated by leaf-MeCBM, leaf metabolism reinforced the physiological response by increasing the internal CO2and then maintaining the normal operation of photosynthetic carbon fixation. We found that phosphoenolpyruvate carboxylase (PEPC) played a crucial role in the accumulation of the internal CO2pool when the CO2uptake rate was limited during stomatal closure. Based on the model simulation, PEPC mechanistically enhanced drought tolerance in cassava by providing sufficient CO2for carbon fixation by RuBisCO, resulting in high production of sucrose in cassava leaves. The metabolic reprogramming decreased leaf biomass production, which may lead to maintaining intracellular water balance by reducing the overall leaf area. This study indicates the association of metabolic and physiological responses to enhance tolerance, growth, and production of cassava in drought conditions.