Water resource shortage and unreasonable application of nitrogen (N) fertilizer have been problems in wheat production of northern China. However, the interaction effects of water regimes and N practices on wheat root growth, grain yield, soil water, and inorganic N changes as well as water-N use efficiency are still unclear under drip irrigation. A field experiment was conducted during the 2020–2021 and 2021–2022 winter wheat (Triticum aestivum) growing seasons. In this study, three irrigation schedules (i.e., irrigation was applied up to 80% [D1], 75% [D2], and 70% [D3] as soon as the soil water content decreased to 65%, 60% or 55% of field capacity) and two N practices (i.e., N applied at the base, jointing, booting stages were 90, 72, 48 kg ha−1 [N1], and the base, jointing, booting, filling stages were 90, 40, 40, 40 kg ha−1 [N2], respectively) were considered. The decease in irrigation water amount was offset by the increase in soil water consumption. In addition, N practices significantly interacted with irrigation on soil NO3−–N accumulation (2021–2022), NH4+–N accumulation, SPAD value (2020–2021), N content in stems and grains at maturity, and average root length and weight density at the flowering stage. Irrigation, rather than N practices, significantly affected grain yield, total N uptake, crop N transformations (NT), the contribution of NT to grain (NTPC), water and N productivity, in which, for the value of these two seasons, D2 increased total N uptake by 18.1% (p < 0.05), and NT by 39.4% (p < 0.05) under N1 as compared to D3. Additionally, the highest WUE and ANUE were found in D2 during 2021–2022. Heavy irrigation water amount caused high a LAI; further analysis proved that the LAI was the key factor affecting grain yield, and positively and significantly correlated to yield. However, no significant difference in the LAI between D1 and D2 was found. N1 was beneficial to prevent N leaching and increase water and N use efficiency, biomass, and N transformation amount. This study recommends that D2 + N1 might be a promising system for manipulating irrigation and fertilization practices under sub-surface drip irrigation systems to improve water and N use efficiency and grain yields in semi-arid regions.
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