Leaf equivalent water thickness (EWT) and dry matter content (expressed as leaf mass per area (LMA)) are two critical traits for vegetation function monitoring, crop yield estimation, and precise agriculture management. Data-driven methods are widely used for remote sensing of leaf EWT and LMA because of their simplicity, satisfactory accuracy, and computation efficiency, such as the vegetation indices (VI)-based and machine learning (ML)-based methods. However, most of the data-driven methods are utilized at the canopy level, comparison of the performances of the data-driven methods at the leaf level has not been well documented. Moreover, the ML-based data-driven methods generally adopt leaf optical properties directly as their inputs, which may subsequently decrease their ability in remote sensing of leaf biochemical constituents. Performances of the ML-based methods cooperating with VI are rarely evaluated. Using the independent LOPEX and ANGERS datasets, we compared the performances of three data-driven methods: VI-based, ML-reflectance-based, and ML-VI-based methods, for the estimation of leaf EWT and LMA. Three sampling strategies were also utilized for evaluation of the generalization of these data-driven methods. Our results evidenced that ML-VI-based methods were the most accurate among these data-driven methods. Compared to the ML-reflectance-based and VI-based methods, the ML-VI-based model with support vector regression overall reduced errors by 5.7% (41.5%) and 1.8% (12.4%) for the estimation of leaf EWT (LMA), respectively. The ML-VI-based model inherits advantages of vegetation indices and ML techniques, which made it sensitive to changes of leaf biochemical constituents and capable of solving nonlinear tasks. It is thus recommended for the estimation of EWT and LMA at the leaf level. Moreover, its performance can further be enhanced by improving its generalization ability, such as adopting techniques on the selection of better wavelengths and definition of new vegetation indices. These results thus provided a prior knowledge of the data-driven methods and can be helpful for future studies on the remote sensing of leaf biochemical constituents.