<p>High-yield wheat production in semi-arid regions suffers from yield-quality antagonism, which is aggravated by excessive nitrogen to compensate for water scarcity. This study aimed to clarify the individual and interactive effects of nitrogen and irrigation on winter wheat’s comprehensive grain quality, and identify the optimal nitrogen-irrigation regime that balances yield, quality and resource use efficiency. A three-year field experiment was conducted in semi-arid China, with 16 nitrogen-irrigation combinations tested. Yield components, flour quality, dough rheology, protein fractions, amino acid composition, water use efficiency, and agronomic nitrogen use efficiency were evaluated. Mixed-model ANOVA, correlation analysis, principal component analysis, hierarchical cluster analysis, quadratic regression, and multi-criteria screening were used. Nitrogen mainly promoted sink formation, grain protein accumulation, amino acid enrichment, and dough rheological improvement, whereas irrigation regulated grain filling, assimilate transport, and grain physical development. Excessive nitrogen increased total protein-related traits but did not continuously improve functional gluten quality, as glutenin accumulation peaked at moderate nitrogen input. The I2N2 regime, corresponding to 210&#xa0;kg N ha^− 1 and 458&#xa0;mm seasonal evapotranspiration, achieved 8,836&#xa0;kg ha^− 1 grain yield, while maintaining superior comprehensive quality and resource-use efficiency. The regression-derived optimum, 258.4&#xa0;kg N ha^− 1 and 453.2&#xa0;mm seasonal evapotranspiration, closely supported the empirically selected I2N2 regime. Synchronized nitrogen-irrigation management can mitigate the yield-quality trade-off by aligning sink capacity, source activity, protein accumulation, and water-mediated grain filling. Moderate nitrogen input with optimized water availability provides a practical pathway for high-yield, high-quality, and resource-efficient wheat production in semi-arid regions.</p> Graphical Abstract <p></p>