Water-driven crop simulation models are often employed to evaluate crop yields and irrigation management strategies for improving agricultural water productivity. Well-tested models can serve as powerful tools for guiding agricultural practices. The objective of this study was to assess the capability of the AquaCrop Model for simulating cotton transpiration and water use under drip irrigation conditions compared with field sap flow measurements. A two-year field experiment (2020–2021) in cotton was conducted in Xinjiang, China, including two row spacings and two topping methods. The model adequately estimated canopy cover with a normalized root mean square error (nRMSE) of less than 5% and a model efficiency (EF) close to 1. The model estimation of transpiration showed good agreement with sap flow measurements (nRMSE=22.4%) across all years and treatments. The model simulated water use efficiency (WUE) values for cotton (4.42 g m^–2 mm^–1) were lower than those calculated from actual measurements with WUE of 4.79 g m^–2 mm^–1. The estimated transpiration was slightly higher than that measured using a sap flow meter due to an 11.5% overestimation of the crop coefficient in the model when cotton grew in a short and dense canopy structure under drip irrigation and plastic film cover conditions. Air temperature, vapor pressure difference and radiation had positive effects on cotton transpiration while humidity had negative effects. The model could capture the trends of transpiration with climatic factors, but the climatic effects were stronger than those of the sap flow observation. In conclusion, the AquaCrop Model is a useful tool for optimizing cotton irrigation strategies.