Addressing water scarcity and soil degradation in the extremely arid region of the southern Tianshan Mountains in Xinjiang, China, requires reducing chemical fertilizer application while maintaining cotton yields, which is crucial for sustainable agricultural development. Method: This study investigated the regulatory effects of partially replacing chemical fertilizers with organic liquid fertilizers on soil nutrients, plant nitrogen uptake, and yield components in cotton fields through a two-year (2024-2025) field trial. Five treatments were established: no nitrogen fertilizer (CK), 100% urea (T1), organic liquid fertilizer replacing 15% (T2), 30% (T3), and 45% (T4) of urea nitrogen. The 30% organic liquid fertilizer replacement treatment (T3) yielded the highest cottonseed cotton production in both years, at 8,375.3 kg & centerdot;ha-1 and 10,014 kg & centerdot;ha-1, respectively, representing increases of 0.7% and 4.81% compared to the conventional fertilization treatment (T1). This treatment exhibited significantly higher agronomic nitrogen use efficiency (ANUE) and partial productivity of nitrogen fertilizer (PFP) than other fertilization treatments. In 2025, ANUE reached 4.34 kg & centerdot;kg-1, ranking highest among all treatments. Regarding plant nitrogen content, T3 treatment showed significantly higher root and leaf nitrogen levels than other treatments during the PBS stage. Simultaneously, soil nitrogen dynamics analysis indicated that the nitrate nitrogen (NO3--N) content in the T3 treatment was significantly higher than that in the T1 treatment, reaching 86.65 mg & centerdot;kg-1 in 2024 and 83.25 mg & centerdot;kg-1 in 2025. Correlation analysis further confirmed that soil nitrate nitrogen content and bolls per plant (NBPT) are key factors influencing seed cotton yield, exhibiting a highly positive correlation. In summary, replacing 30% of chemical fertilizer nitrogen with organic liquid fertilizer nitrogen in drip-irrigated cotton fields not only optimizes soil nitrogen supply but also enhances nutrient use efficiency. This approach achieves dual objectives of increased yield and sustainable production, providing scientific basis for integrated water and fertilizer management in extreme arid regions.