Crops are constantly challenged by different environmental conditions. Seed treatment using nanomaterials is a cost-effective and environmentally friendly solution for environmental stress mitigation in crop plants. Here, 56 seed nanopriming treatments are used to alleviate environmental stresses in maize. Seven selected nanopriming treatments significantly increase the stress resistance index (SRI) by 13.9% and 12.6% under salinity stress and combined heat-drought stress, respectively. Metabolomics data reveal that ZnO nanopriming treatment, with the highest SRI value, mainly regulates the pathways of amino acid metabolism, secondary metabolite synthesis, carbohydrate metabolism, and translation. Understanding the mechanism of seed nanopriming is still difficult due to the variety of nanomaterials and the complexity of interactions between nanomaterials and plants. Using the nanopriming data, we present an interpretable structure-activity relationship (ISAR) approach based on interpretable machine learning for predicting and understanding its stress mitigation effects. The post hoc and model-based interpretation approaches of machine learning are integrated to provide complementary advantages and may yield more illuminating or trustworthy results for researchers or policymakers. The concentration, size, and zeta potential of nanoparticles are identified as dominant factors for correlating root dry weight under salinity stress, and their effects and interactions are explained. Additionally, a web-based interactive tool is developed for offering prediction-level interpretation and gathering more details about a specific nanopriming treatment. This work offers a promising framework for accelerating the agricultural applications of nanomaterials and may contribute to nanosafety assessment.