Irrigation and fertilization are the most effective measures to inhibit soil salt accumulation and increase yield of wheat (Triticum aestivum L.) grown in saline soils. The present study used a split-plot experimental design with irrigation as the main plot and fertilizer application as the subplot from 2014 to 2016. The experiment had four levels each of irrigation (W0, no irrigation; W1, one irrigation; W2, two irrigations; W3, three irrigations) and fertilization (M, no fertilizer; Y, cow manure; W, chemical fertilizer; and H, 50% cow manure and 50% chemical fertilizer). The study identified sowing, jointing, and maturity as the major salt accumulation periods. After irrigation, the 0-to 20-cm soil salinity during presowing, jointing, and grain filling decreased by 1.09, 0.28, 0.19 g kg −1 , and 0.76, 0.46, and 0.23 g kg −1 , from 2014 to 2016. The wheat roots were mainly distributed in the 0-to 30-cm soil layer. Meanwhile, wheat evapotranspiration (ET) ranged from 153 to 402 and 202 to 451 mm from 2014 to 2016, respectively; and the ET under W3W were 2.62-and 2.23-times higher than W0M. Additionally, W3W increased yield of wheat by 567.0 and 422.2% from 2014 to 2016, compared with W0M. Generally, the water use efficiency (WUE) decreases as irrigation increases; however, this study found no significant difference in WUE between W2 and W3. Meanwhile, the chemical fertilizer resulted in the highest WUE, 3.16-and 2.63-times higher than no fertilizer.Thus, the study proposes W3W as a suitable treatment for wheat in the Yellow River Delta.