Understanding the interaction effects of water, fertilizer, and salinity is of great environmental importance to mitigate soil salinization and improve crop production. Field experiments were conducted to evaluate the effects of water quality, irrigation amount, and nitrogen application rate on soil salt accumulation, root water and nitrogen uptake, lint yield, and water productivity during 2018 and 2019 growing seasons of cotton (Gossypium hirsutum L.) in arid region of Xinjiang, China. Four irrigation levels 75%, 100%, 125%, and 150% of crop water requirement (ET_c) and four nitrogen levels 195, 255, 315, and 375 kg ha⁻¹ were applied with groundwater and brackish water irrigation. Results demonstrated that, brackish water irrigation significantly increased the root-zone soil salt accumulation (SSA). Either increasing irrigation amount during the squaring stage or decreasing irrigation amount during the flower boll stage with higher nitrogen application rate can reduce the SSA. And with an increase in brackish water irrigation amount, a corresponding increase in nitrogen application rate is required to reduce the possible soil salt accumulation during the flower boll stage. Highest irrigation amount (150% ET_c) and nitrogen application rate (375 kg ha⁻¹) at the flower boll stage and during the whole growing season resulted in significant higher nitrogen uptake increment with an increasing rate of 25–74% and 39–65%, respectively. The integration of higher irrigation amount and highest nitrogen application rate with groundwater irrigation produced higher lint yield and water productivity. Considering soil salinity and lint yield as well as water productivity, the appropriate integration modes of water and nitrogen are higher irrigation amount and highest nitrogen application rate (125% ET_c and 375 kg ha⁻¹) for groundwater and lowest irrigation amount and lower nitrogen application rate (75% ET_c and 255 kg ha⁻¹) for brackish water.