Nitrogen (N), phosphorus (P), and potassium (K) are important nutrients limiting cotton yield. Although N, P, and K fertilization is an important practice for improving cotton productivity, their fertilizer use efficiencies remain insufficiently evaluated in Xinjiang, China. In this study, field experiments were conducted at 57 sites across the major cotton-growing areas of Xinjiang during 2021–2022. Four fertilization treatments, PK, NK, NP, and NPK, were established to evaluate cotton yield response, nutrient accumulation, and fertilizer use efficiencies of N, P, and K under different soil fertility conditions. The results indicated that the cotton yield in both southern and northern Xinjiang significantly increased under NPK treatment, with mean yields of 6300 and 7361 kg ha
−1, respectively. The use efficiencies of N, P, and K were 39.8%, 19.5%, and 51.4% in southern Xinjiang, and 40.3%, 20.2%, and 66.1% in northern Xinjiang, respectively. For every 100 kg of seed cotton produced, nutrient uptake was 4.64 kg N, 1.43 kg P
2O
5, and 3.67 kg K
2O in southern Xinjiang, and 4.74 kg N, 1.48 kg P
2O
5, and 4.58 kg K
2O in northern Xinjiang, indicating relatively high N and K requirements but lower P demand in cotton production. Cotton yield in southern Xinjiang was significantly and positively correlated with soil alkali-hydrolyzable N. In northern Xinjiang, cotton yield was significantly and positively correlated with soil organic matter, alkali-hydrolyzable N, and available K, but negatively correlated with available P. Overall, cotton yield was mainly positively affected by soil organic matter, alkali-hydrolyzable N, and available K, whereas K use efficiency was significantly and negatively correlated with N and K rates. The suitable N, P, and K rates for cotton were 285, 120, and 106 kg ha
−1 in southern Xinjiang, and 243, 101, and 91 kg ha
−1 in northern Xinjiang, respectively. Based on soil fertility classification of cotton fields, the recommended N, P, and K rates were 256–313, 96–117, and 125–153 kg ha
−1 in southern Xinjiang, and 219–267, 97–119, and 136–166 kg ha
−1 in northern Xinjiang, respectively. Accordingly, reducing N and P inputs in southern Xinjiang, maintaining N and P at appropriate levels in northern Xinjiang, and moderately increasing K are recommended to achieve coordinated improvements in yield stability and N, P, and K use efficiencies.
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