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Irrigation, fertilization, and variety are important factors affecting potato production in northwest China. Field experiments (2021 and 2022) were performed to investigate the effects of irrigation and fertilization on the plant growth and soil microbial population of different potato varieties. Three irrigation levels were used, i.e., 100% ETc (W1), 80% ETc (W2), and 60% ETc (W3), with ETc standing for crop evapotranspiration. Three fertilization levels were used (N-P-K), i.e., 240-120-300 kg ha−1 (F1), 180-90-225 kg ha−1 (F2), and 120-60-150 kg ha−1 (F3). Three variety types were used, i.e., Feiurita (V1), Longshu 7 (V2), and Qingshu 9 (V3). These factors significantly influenced tuber yield (TY), net income (NI), and water productivity (WP). TY, NI, WP, total nitrogen accumulation (TNA), and nitrogen use efficiency (NUE) peaked at F2. Fertilization significantly impacted soil bacteria quantity (SBQ), fungi quantity (SFQ), and actinomycetes quantity (SAQ). TY, NI, SBQ, SFQ, and SAQ were highest at W2. Soil microbial population was strongly correlated with TY, NI, WP, TNA, and NUE. Comprehensively, this study suggests that irrigation that is varied from 248 to 266 mm, and fertilization (N-P-K) that is varied from 149.09-74.55-186.36 to 212.73-106.36-265.91 kg ha−1 can promote the potato industry's sustainable development and provide important references for the optimal field management of potato cultivation in northwest China. [ABSTRACT FROM AUTHOR]