(1) Background: Accurate inversion of crop water content is key to making an intelligent irrigation decision. However, little effort has been devoted to accurately estimating the crop water content of winter wheat in the North China Plain. (2) Method: The crop water content of winter wheat was measured at jointing, flowering and grain-filling stages, respectively. UAV-based multispectral remote sensing images were used to calculate thirteen vegetation indices, including SAVI, EVI, R-M, NDRE, OSAVI, GOSAVI, REOSAVI, GBNDVI, NDVI, RVI, DVI, GNDVI, and TVI. Five machine learning (ML) algorithms (i.e., MLR, RF, PLSR, ElasticNet, and ridge regression) were adopted to estimate the crop water content of winter wheat at the three growth stages. The benchmark datasets, which include CWC as well as vegetation indices calculated based on spectral indices, were adopted to validate the performance of the ML models. (3) Results: The correlation coefficients ranged from 0.64 to 0.82 at different growth stages. The optimal vegetation indices were GNDVI for the jointing stage, NDRE for the flowering and the grain-filling stage, respectively. Among the five machine learning methods, random forest (RF) showed the best performance across the three growth stages, with its coefficient of determination (R2) of 0.80, or an increase by 20.1% than those of other models. In addition, the RMSE and RPD of the RF model at the flowering stage were 3.00% and 2.01, which significantly outperformed other models and growth stages. (4) Conclusion: This study may provide theoretical support and technical guidance for monitoring current water status in wheat crops, which is useful to develop a precise irrigation prescription map for local farmers. (5) Limitation: The main limitation of this study is that the sample size is relatively small and may not fully reflect the characteristics of the target groups. At the same time, subjectivity and bias may exist in the data collection, which may have a certain impact on the accuracy of the results. Future studies could consider expanding sample sizes and improving data collection methods to overcome these limitations.