Food security and the depletion of water resources have become the two main concerns for the future of agricultural sustainability. Climate change, on the other hand, challenges global agricultural productivity, making target agricultural zones less productive. However, increasing yield potential through adaptation is crucial for improving global agricultural production. In this study, an approach for studying the impacts of future climate conditions and adaptation strategies on yield and water use dynamics of maize in the Eastern Kansas River Basin (EKSRB) of the US Great Plains, based on different future climate scenarios and deficit irrigation water management at a 4 km spatial resolution was presented. Using the spatially-adapted CERES-Maize model, the combination of impacts ofin silicogenotype-specific adaptations for selected genotype-specific parameters, treated as quantitative traits (improved canopy photosynthesis for radiation use efficiency [RUE], light extinction [KCAN], and heat tolerance [HEAT]), and agronomic management (shifting planting window [PD1 & PD2], and no nutrient limitation [NNL]) on yield and irrigation water use were explored. In addition, we assessed the integration of the individual genotype-specific and agronomic adaptation strategies to understand the co-benefits and trade-offs on yield improvement and water savings. Future climate scenarios for the region were created for two Representative Concentration Pathways (RCPs) (4.5 and 8.5) over three 25-year future periods (2025–2100) and compared to the historical climate (1991–2015). Results showed that future maize yield declined by approximately 34 % to 43 % (early and late century time periods, respectively) under RCP 4.5, and 33 % to 68 % (early and late century time periods, respectively) under RCP 8.5. Despite the yield declines, we found water use savings ranging from 9 % to 20 % (early and late century time periods, respectively) under RCP 4.5, and 13 % to 18 % (early and late century time periods, respectively) under RCP 8.5. We observed that integrated adaptation strategy linked to improved RUE, HEAT, KCAN, NNL, and PD2 (INT-NNL-PD2; Int 4), resulted in the early 21st century average yield gain of 0.6 to 3 % (RCPs 4.5 and 8.5, respectively), with water savings of 10 to 13 % (RCPs 4.5 and 8.5, respectively), relative to historical condition. However, going forward into the 21st century, we found marginal yield deviations (especially under RCP 4.5) with further increases in water savings, more than observed under the no-adaptation scenario. This suggests the need to re-examine and re-design these adaptation strategies for further yield improvement, while leveraging the benefits of water savings under future climate conditions. Our findings emphasize the transformative potential of all-inclusive integrated adaptation strategies in mitigating the impacts of future climate conditions on irrigated maize production in the Great Plains.