Groundwater contamination by nitrate-nitrogen (NO3–N) under intensive agriculture is increasingly receiving worldwide attention. However, knowledge of the potential effects of different irrigation strategies coupled with nitrogen applications on groundwater under intensive agricultural practices remains a critical issue and a grand challenge due to the long transit time for NO3–N across the thick vadose zone. To close this knowledge gap, the calibrated RZWQM2 model was used to investigate long-term (1970–2070) water and NO3–N dynamics in the vadose zone and the potential threat of NO3–N pollution on groundwater under different irrigation strategies (35% of total available water-triggered, 100% filled irrigation (I35% TAW), 90-mm irrigation (I90 mm), and 150-mm irrigation (I150 mm)) and nitrogen applications (optimal and conventional high rates) for the maize-wheat rotation system in the Jinghui Canal irrigation area of the Guanzhong Plain in China. Results showed that mean groundwater recharge values were 43, 65, and 271 mm yr−1 under the I35% TAW, I90 mm, and I150 mm scenarios, respectively, with no significant effect on crop yields. Accumulated NO3–N was concentrated at the 10-m depth over the past 50 years and would be deeply transported to the 15-m and 20-m depths under the I35% TAW and I90 mm strategies, respectively, in the future 50 years. Accumulated NO3–N was concentrated uniformly at the 30-m depth for the I150 mm scenario, with NO3–N amounts of 85.8 and 26.9 kg ha−1 yr−1 leached into the groundwater (30 m) under the conventional and optimal nitrogen applications. Although groundwater at 8–10 m faced the risk of NO3–N pollution during the past 50 years, and groundwater at the deeper depths of 15–20 m could be threatened in the next 50 years under the I35% TAW and I90 mm strategies, the annual amount of NO3–N leaching into groundwater could be significantly reduced from 68.9 to 71.8 kg ha−1 to 10.3–12.7 kg ha−1 by applying more optimal amounts of nitrogen. The results of this study provide a straightforward understanding of long-term spatial and temporal characteristics of water and NO3–N in the vadose zone, and provide insight into possible methods for controlling irrigation application amounts that would prevent groundwater pollution from NO3–N in irrigated areas.