A Soil and Water Assessment Tool (SWAT) model was selected to simulate the dynamic changes of water and fertilizer migration, and crop yields under different tillage modes and soil salinization levels. The Hetao Irrigation District with the complex spatial variability of soil salinity were taken as the research object, where three areas were divided: Jiefangzha, Yongji, and Yichang irrigation area. Some parameters were utilized for the simulation and verification of the model, including eight runoff and seven nitrate-nitrogen variables. At the same time, five parameters of crop growth were selected using the existing research. Finally, the specific values of each variable were measured at the outlets of irrigation areas. The soil types were also the cumulic anthrosols and mollic solonchaks in the study area. Four salinity levels were set under the two soil types, according to the grades of non-salinized soil (S1), lightly salinized soil (S2), moderately salinized soil (S3), and heavily salinized soil (S4). At the same time, five farming treatments were selected in the long-term farming mode: no-tillage management (CK), no tillage (T1), less tillage (T2), conventional spring tillage (T3), and template plowing (T4). A systematic investigation was then made on the effects of tillage modes and soil salinization on water production, crop nitrogen uptake, nitrate-nitrogen leaching and transportation, as well as the crop yields in the irrigation areas. As such, the salinized soil was be adjusted to reduce environmental pollution, while promoting the grain production, and the sustainable development of agriculture. The results show that the SWAT model with the calibrated parameters performed better than before to directly verify the runoff and nitrate nitrogen, where the determination coefficient R2, and the efficiency coefficient were not less than 0.69 and 0.58, respectively, while the absolute value of the Relative Error (RE) was less than 10%. The simulated and measured crop yields were basically distributed near the 1:1 line, where the efficiency coefficient and R2 values in the calibration and validation period were not less than 0.93 and 0.94, respectively, and the RE absolute value was less than 4%. The validated SWAT model presented an excellent performance to simulate the water production, nitrate-nitrogen transport, and crop yield in the irrigation areas. There were some significant effects of tillage modes and soil salinity on the total regional water production, crop nitrogen uptake, nitrate-nitrogen leaching, nitrate-nitrogen transport, and crop yield (P<0.05). Among them, the regional water production, nitrate-nitrogen leaching, nitrate-nitrogen transport run in different hydrological paths, whereas, the wheat yield gradually decreased, with the increase of tillage mixing depth and efficiency. The amount of nitrogen uptake by crops and the yield of corn and sunflower gradually increased, with the increase of mixing depth and efficiency. The nitrogen uptake of template plowing crops increased by 11.78% on average, and the nitrate-nitrogen leached volume was reduced by 16.5% on average, indicating an effective reduction in the soil nutrient loss and groundwater pollution. In addition, the output of maize and sunflower increased but the output of wheat decreased, compared with no-tillage treatment. The increase in the soil salinity significantly increased the total regional water production, and nitrate-nitrogen leaching (except for the Mollic Solonchaks). The effective water holding capacity of the soil layer greatly contributed to reducingthe underground nitrate nitrogen transport, as well as the amount of crop nitrogen uptake and crop yield. The yields of wheat, maize, and sunflower in the treatment of heavily saline soil were significantly reduced by 19.15%, 27.31%, and 26% on average (P<0.05), compared with non-salinized soil. There was a more significant impact of soil salinity on the regional water production, soil nutrients, and crop yields, compared with the tillage modes. Therefore, a strong recommendation can be addressed to focus on the prevention, control, and treatment of regional soil salinization, in order to better manage the serious pollution in the irrigation areas and crop yields. This finding can also provide a theoretical basis for the sustainable development of agriculture in the Hetao Irrigation District.