Recently, to achieve the goal of increasing both crop yield and water/nitrogen use efficiency with a better irrigation regime is a major challenge in semi-arid areas. In this study, we presented a two seasonal-field experiment that considers irrigation regimes, i.e., no irrigation (W0), irrigated in jointing (W1), both in jointing and flowering (W2) after the re-greening, and varieties (S086; J22) to compare the response of the sensitivity of wheat leaf physiological indicators, yield, water/N use efficiency and soil water consumption to irrigation regimes. The results showed that the WUE, IWUE and soil water-holding consumption (SWC) decreased with the increase in amount of irrigation. Additionally, 45.5% of the excessive irrigation water input did not promote wheat yield (W1 vs. W2). The degree of SWC in the 0–120 cm soil layer was highly related to wheat growth. S086 was beneficial for the usage of SWC under a low amount of irrigation. As well, irrigation positively affected the activities of superoxide dismutase (SOD) and catalase (CAT) in the flag leaf (P<0.05) during crop yield production. A decrease of irrigation helped to increase the concentrations of SS and Pro and decrease of amount of MDA for S086. Thus, a high yield of S086 was found under deficit irrigation (W1, a 31.3% reduction of irrigation water than that of W2). Thus, our studies suggested that one irrigation event in jointing stage for the S086 variety was essential to meet the win-win goal of high crop yield and water use efficiency with low groundwater consumption.