In the middle reach of the Yangtze River Plain, cotton (Gossypium hirsutum. L) can experience aeration stress at multiple growth stages, often accompanied by high temperature. These two stresses can negatively affect growth and yield. This study aimed to investigate the responses of cotton at different growth stages to aeration stress, particularly under high temperature. Two field experiments examining cotton responses to aeration stress were conducted over 8 yr, and structural equation modeling was performed to reveal the relationships among aeration stress, high temperature, and the growth and yield of cotton at four growth stages. The interannual variability in the yield‐reducing effect of aeration stress was closely associated with high temperature. Aeration stress and high temperature both interactively (in Experiment 1) and independently (in Experiment 2) reduced seed cotton yield. The interaction between these two stresses was observed only in Experiment 1, in which the impact of aeration stress was relatively slight. In Experiment 1, the growth stage most sensitive to aeration stress changed with high temperature. In both experiments, under high temperature, the sensitivity of seed cotton yield to aeration stress was threefold higher at the flowering and boll‐filling stage than at the other stages. In conclusion, the responses of cotton to aeration stress depend on the time at which aeration stress occurs and the additional impact, if any, of high temperature.