Soil salinity affects the yield and quality of cotton (Gossypium hirsutum L.) under drip irrigation in arid regions. Coupled effects of initial soil salinity and heterogeneous irrigation water quality exacerbate salinity changes, thereby heightening the challenges to robust nitrogen (N) management strategies and to stable cotton yield. To determine the threshold soil salinity (Sth) for cotton and the appropriate nitrogen application rate under different combinations of water quality and initial soil salinity, a field experiment was conducted in Xinjiang, China during the 2019 and 2020 cotton growing seasons under drip irrigation. The experiment evaluated the combined effects of initial soil salinity, water quality, and nitrogen application rate on soil salinity changes, plant nitrogen uptake and leaf area index (LAI), as well as cotton yield and quality. Two irrigation water qualities (groundwater (G) and brackish water (B)), three initial soil salinities (slight-saline (S1), moderate saline (S2) and strongly saline (S3)) and three N application rates (255 kg ha(-1) (F1), 315 kg ha(-1) (F2) and 375 kg ha(-1) (F3)) were designated in the experiment. The results revealed that G irrigation reduced the soil salt content of S2 and S3 by 26.2 % and 30.2 %, respectively. The soil salt content increased by 1.1-2.9 g kg(-1) under brackish water irrigation, whereas a high nitrogen application rate (F3) decreased the soil salt content. Based on K-value clustering analysis and the linear relationships between growth, yield and quality and the soil salt content, the Sth of cotton was 4.0 g kg(-1). Under the aforementioned threshold soil salinity, to further maintain high nitrogen use efficiency, the recommended N application rate of 255 kg ha(-1) under groundwater irrigation when initial soil salinity is <= 4.8 g kg(-1), and 315 kg ha(-1) under brackish water irrigation when initial soil salinity is <= 2.3 g kg(-1). These N application strategies enhanced cotton production while avoiding fertilizer waste and environmental issues.