Hydrophobic interactions drive numerous biological and synthetic processes. The materials used in these processes often possess chemically heterogeneous surfaces that are characterized by diverse chemical groups positioned in close proximity at the nanoscale; examples include functionalized nanomaterials and biomolecules, such as proteins and peptides. Nonadditive contributions to the hydrophobicity of such surfaces depend on the chemical identities and spatial patterns of polar and nonpolar groups in ways that remain poorly understood. Here, we develop a dual-loop active learning framework that combines a fast reduced-accuracy method (a convolutional neural network) with a slow higher-accuracy method (molecular dynamics simulations with enhanced sampling) to efficiently predict the hydration free energy, a thermodynamic descriptor of hydrophobicity, for nearly 200 000 chemically heterogeneous self-assembled monolayers (SAMs). Analysis of this dataset reveals that SAMs with distinct polar groups exhibit substantial variations in hydrophobicity as a function of their composition and patterning, but the clustering of nonpolar groups is a common signature of highly hydrophobic patterns. Further molecular dynamics analysis relates such clustering to the perturbation of interfacial water structure. These results provide new insight into the influence of chemical heterogeneity on hydrophobicity via quantitative analysis of a large set of surfaces, enabled by the active learning approach.