Water limitation and nitrogen (N) availability interact antagonistically to constrain maize productivity, yet this critical relationship remains poorly quantified in semi-arid cropping systems. Using maize (Zea mays L.) as a model crop, we conducted a three-year (2021-2023) field experiment in the US Great Plains with two irrigation regimes (100% and 70% of plant evapotranspiration targets) and six N availability levels (50-327 kg N ha-1, including fertilizer, irrigation, and residual soil inorganic N). Under full irrigation, maize grain yield and aboveground biomass increased with N availability. In contrast, excess N was detrimental under water-limited conditions, reducing grain yield, aboveground biomass, and root biomass relative to moderate N rates. Maximum grain yield under water limitation required, on average, 31% less N than under full water. Water limitation decreased maximum yields by 36%, 59%, and 30% in 2021, 2022, and 2023, respectively. Notably, yield reductions at high N availability persisted in 2023 despite lower fertilizer inputs due to residual soil N carryover. Nitrogen uptake increased with N supply and was higher under full irrigation; however, under water stress, elevated N uptake became decoupled from yield and biomass production. These results demonstrate that matching N inputs to water-limited yield potential is essential to maximize grain yield and resource-use efficiency. Adjusting N inputs based on soil N availability and yield potential will become increasingly critical as water scarcity intensifies in semi-arid cropping systems.