Agricultural irrigation consumes most of the fresh water in the China–Pakistan Economic Corridor (CPEC), directly affecting water resource management and allocation. Irrigation water demand is a key component of regional water resources management. We analyzed spatiotemporal variation in irrigation water requirement, irrigation demand index (IDI), and the proposed regional optimization of irrigation water use based on the Bayesian probability network. Results showed that: (1) The IDI in the study area increased slightly (trend slope = 0.028 a−1) as the effective precipitation increased by 63% during this period, and total irrigation water requirement (IR) decreased from 277.61 km3 in 2000 to 240 km3 in 2015. (2) Cotton had the highest crop IDI, followed by maize and wheat. (3) According to the comprehensive scenario analysis, improving the crop planting structure (by moderately increasing the planting proportion of maize in the CPEC) is conducive to improving regional water and food security by enhancing the grain yield (+ 9%), reducing the malnourished proportion of the population (low state + 7.2%), and bolstering water-saving irrigation technologies in Pakistan as well as water conveyance systems in Pakistan. Our results form an important baseline in determining the way forward on sustainable water resource utilization management in the CPEC.