Irrigation and nitrogen application directly affect the availability and distribution of soil nutrients. Understanding the response of soil nutrients to long-term water–fertilizer coupling conditions is helpful to improve the management and use efficiency. Irrigation was divided into three gradient levels, which accounted for 45%, 60%, and 75% (W1, W2, and W3) of the field water holding capacity. Based on pure nitrogen, four levels of nitrogen application were set: 0.0, 101.6, 203.2, and 304.8 kg·hm−2 (N0, N1, N2, and N3). We measured tree height and diameter at breast height (DBH), and we analyzed the chemical properties of the soil at 0–40 cm depth, from 2007 to 2020. The ranges of DBH, tree height, individual volume, and stand volume were 5.80–25.25 cm, 6.10–16.47 m, 0.01–0.37 m3, and 11.76–481.47 m3·hm−2, respectively. The contents of organic matter, total nitrogen, available phosphorus, and available potassium in the soil ranged from 8.60 g·kg−1 to 18.72 g·kg−1, from 0.21 g·kg−1 to 0.79 g·kg−1, from 8.09 mg·kg−1 to 47.05 mg·kg−1, and from 90 mg·kg−1 to 322 mg·kg−1, respectively. Soil pH value decreased rapidly at a rate of 0.31 units per year for the first five years. Irrigation and nitrogen application, and their interaction, had significant (p < 0.01) effects on soil total nitrogen, available phosphorus, available potassium, and nitrate-nitrogen. We suggest maintaining the field water holding capacity above 60%, with a nitrogen application rate of 203.2 kg·hm−2, to save water, maintain soil fertility, and optimize soil nitrogen supply. Our study aimed to achieve scientific and accurate fertilization of Populus tomentosa stands over different periods, to alleviate the decline of soil fertility, and to improve the utilization rate of water and fertilizer through long-term nutrient monitoring.