Abstract: Xinjiang has been one of the major cotton-producing areas in China. The yield and quality of cotton have been seriously limited to irrigation and fertilization, as well as the use efficiency of water and fertilizer resources. Irrigation, nitrogen fertilization, and mepiquat chloride have been widely used in the cotton production in recent years. This study aims to explore the interactive effects of irrigation amount, nitrogen rate, and mepiquat chloride dose on seed cotton yield, fiber quality, and water-fertilizer use efficiency. The field experiments were also carried out in the Korla region of Southern Xinjiang in 2020 and 2021, including three irrigations (W₁: 60%ET_c, W₂: 80%ET_c, and W₃: 100%ET_c, where ET_c was the crop evapotranspiration), four nitrogen rates (N₀: 0 kg/hm², N₂₀₀: 200 kg/hm², N₃₀₀: 300 kg/hm², and N₄₀₀: 400 kg/hm²), and two doses of mepiquat chloride (D₁: 120 g/hm², and D₂: 240 g/hm²). The planting mode was adopted as "one film, two pipes, and four rows". The fertilizer was dissolved in the irrigation water eight times for drip fertilization. The foliar spraying of mepiquat chloride was conducted using a manual knapsack sprayer. Some indicators were measured (such as the plant height, leaf area index, dry matter accumulation, seed cotton yield, and fiber quality) to calculate the crop evapotranspiration, water use efficiency, and partial factor productivity of fertilizer. The results showed the irrigation amount, nitrogen rate, and mepiquat chloride dose significantly dominated the seed cotton yield, water use efficiency, partial factor productivity of fertilizer, and some indicators of fiber quality (P<0.05). Furthermore, their three-factor interaction also depended on the partial factor productivity of fertilizer and fiber quality (P<0.05). The irrigation amount increased the plant height, leaf area index, and dry matter accumulation, while the trend of nitrogen rate was the first increase and then decrease. The leaf area index of each treatment showed an S-shaped curve, as the growth period progressed, thus increasing rapidly during the seedling and bud stages, and then reaching a peak at the flowering stage. Plant height and leaf area index decreased, whereas, the dry matter accumulation increased when the dose of mepiquat chloride increased from 120 to 240 g/hm². The effective boll number of D₁ increased with the increase in the nitrogen rate, while the effective boll number of D₂ increased first and then decreased. The increasing irrigation amount and mepiquat chloride dose improved the boll weight and seed cotton yield, while the nitrogen rate led to the increasing boll weight, but with increasing and then decreasing seed cotton yield. The W₃N₃₀₀D₂ had the highest dry matter accumulation, effective boll number per plant, and seed cotton yield. The W₃N₃₀₀D₁ had the highest plant height and leaf area index. The maximal seed cotton yield (7 578 kg/hm² in 2020 and 7 173 kg/hm² in 2021) occurred in W₃N₃₀₀D₂. The partial factor productivity of fertilizer increased, while the water use efficiency decreased, as the irrigation amount increased. The mepiquat chloride dose improved the water use efficiency and partial factor productivity of fertilizer. The highest performance was achieved in the water use efficiency of W₁N₄₀₀D₁ and the partial factor productivity of fertilizer of W₃N₀D₂. Fiber length increased with the increasing nitrogen rate under W₁ and W₂. There was the first increase and then a decrease with the increase of nitrogen rate under W₃, where the maximum was obtained under N₃₀₀. The mepiquat chloride dose also decreased the fiber strength and micronaire value. The fiber length, fiber strength, and micronaire value of W₃N₄₀₀D₂ were all obtained from the larger values, where the fiber quality was the best. Six indicators were selected from three aspects (yield, water-fertilizer use efficiency, and fiber quality) in the TOPSIS evaluation. The best combination was achieved in the irrigation amount of 100%ET_c, nitrogen rate of 300 kg/hm², and mepiquat chloride dose of 240 g/hm², suitable for the water-fertilizer and chemical control practice of cotton in southern Xinjiang. The findings can provide a theoretical basis and scientific guidance for the efficient utilization of water and fertilizer in cotton production in southern Xinjiang China.