Mulch drip irrigation has great benefits to save water for high cotton production in Xinjiang, China. Among them, freshwater has widely been used in agricultural irrigation. Highly efficient exploitation and utilization of saltwater resources have been the potential urgent to alleviate the ongoing freshwater shortages. In this study, a three-year growing season field experiment was conducted with different salinity level water irrigation, thereby analyzing the soil salt content within the different soil layers during the whole growth period of cotton. A salinity threshold of cotton was determined under saltwater mulch drip irrigation. An HYDRUS-2D model of soil salt was also built in cotton field under saltwater drip irrigation using the theory of soil water and solute movement. A numerical simulation was conducted for the distribution and accumulation characteristics of soil salt. The experiment was carried out in Shihezi University, China. The base presented an average altitude of 450.8 m and a geographical location of 85°59′47″ E, 44°19′26″ N. Cotton was planted in each plot with the size of 2 m × 2 m× 2 m. The irrigation water was treated with five salinity levels: 2, 3, 4, 5, and 6 g/L. The ratio of chemicals NaHCO3, Na2SO4, NaCl, CaCl2, and MgCl2 were 1:7:8:1:1, according to the composition of local groundwater. The results showed that: 1) The salt accumulated less under 2, 3, and 4 g/L salinity treatments, where the plant height, chlorophyll, and yield of cotton were higher than those under 5 and 6 g/L salinity treatments. Therefore, 4 g/L salinity level was the threshold of irrigation water. 2) The soil salt gradually accumulated with the growth period of irrigationand reached the peak at the opening period. The soil electrical conductivity at the emitter increased at first and then decreased with the peak value in 60-70 cm soil layer, as the soil depth increased. The soil electrical conductivity of different salinity treatments were 3.04, 3.18, 3.15, 3.00, and 3.12 dS/m, respectively. 3) There was a more obvious accumulation trend with the increase in the salinity of irrigation water sources. The simulated salt accumulation was ranked in the order of 30 cm > 50 cm > 10 cm soil layers. There was in good agreement, where the Mean Absolute Error of (MAE)<0.168, Mean Relative Error of (MRE)< 15.321, root mean square error of (RMSE)<0.2, Coefficient of determination R2>0.79 between the measured and simulated values of different soil layers. Therefore, the 4 g/L salinity level was suitable for the mulch drip irrigation of cotton using saline water. The finding can provide promising guidance for further exploitation and utilization of saltwater resources, particularly for the sustainable development of irrigated agriculture in semi-arid and arid areas.