Abstract: This study aims to explore the three-factor interaction of the irrigation amount, combined application of the organic and inorganic fertilizers, and fulvic acid on the soil fertility and cotton growth under drip irrigation. A field experiment was conducted under mulch in Xinjiang in 2024. A three-factor randomized experiment consisted of 18 treatments in total. Three irrigation levels were set as follows: 4 500 m³/hm² (W1), 3 825 m³/hm² (W2), and 3 150 m³/hm² (W3). Three levels of the combined organic-inorganic fertilizer application with the equal nitrogen content were established: no organic fertilizer + 600 kg/hm² urea (O1), 2 000 kg/hm² organic fertilizer + 510 kg/hm² urea (O2), and 4,000 kg/hm² organic fertilizer + 420 kg/hm² urea (O3). Two levels of the fulvic acid were included: no fulvic acid addition (F1) and 45 kg/hm² fulvic acid addition (F2). The indicators were also obtained, such as the soil water and nutrient parameters, crop growth, yield and quality, as well as the water and fertilizer use efficiency. A precise scheme was proposed for the cotton irrigation and fertilization, in order to achieve the water conservation, stable yield, and efficiency. The results showed that the fulvic acid addition increased the soil water storage at the seedling stage under the same irrigation amount and combined organic-inorganic fertilizer treatment, compared with the treatment without the fulvic acid. While there was a decrease at the flowering and boll-forming stage. The interaction between irrigation amount and fulvic acid also showed a threshold effect on the soil water storage and organic matter content. Specifically, the soil water storage increased by 7.83% and 18.02%, respectively, in the W1 and W2 treatments with the fulvic acid addition at the budding stage, compared with those without the fulvic acid, while that decreased by 6.32% in the W3 treatment. At the end of the growing season, the organic matter content increased by 30.30% and 80.40%, respectively, in the 0–20 cm soil layer of the W1 and W2 treatments with the fulvic acid addition, whereas that decreased by 17.68% in the W3 treatment. The interaction between combined organic-inorganic fertilizer application and fulvic acid shared a threshold effect on the boll dry matter weight. Compared with the treatment without the fulvic acid, the boll dry matter weight increased by 22.51% and 23.69%, respectively, in the O1 and O2 treatments with the fulvic acid addition, while that decreased by 25.57% in the O3 treatment. The three-factor interaction between the irrigation amount, combined application of the organic-inorganic fertilizer, and the fulvic acid also presented a threshold effect on the cotton yield, partial factor productivity of the nitrogen fertilizer, and irrigation water use efficiency. Under the O3 condition, the cotton yield, partial factor productivity of the nitrogen fertilizer, and irrigation water use efficiency were all improved in the W1 and W2 treatments with the fulvic acid addition, compared with those without fulvic acid, while those decreased in the W3 treatment. An evaluation was conducted with the equal weights of the cotton yield, cotton quality index, irrigation water use efficiency, and partial factor productivity of the nitrogen fertilizer under each treatment using the Technique for Order Preference by Similarity to an Ideal Solution. The W1O2F2 treatment was identified as the best irrigation and fertilization for the yield and efficiency enhancement. The W2O1F2, W2O2F2, and W3O3F1 treatments were all achieved in the water conservation, stable yield, and efficiency in the arid and semi-arid regions. The findings can provide a theoretical basis and data support for the water-saving and high-efficiency cultivation of the cotton during drip irrigation under mulch in the arid and semi-arid regions.