Applying nano-delivery systems for phytohormones via foliar application has proven effective in reducing grain cadmium (Cd) levels in crops. However, the mechanisms underlying this reduction remain inadequately understood. This study integrated the determination of leaf photosynthetic parameters, Cd translocation analysis, and metabolomics to elucidate the effects of reduced glutathione (GSH) and melatonin (MT), delivered with or without chitosan-encapsulated mesoporous silica nanoparticles (MSN-CS), on grain Cd levels in rice. Our findings revealed that the foliar application of MT@MSN-CS significantly outperformed MT alone in reducing grain Cd levels and enhancing leaf photosynthesis under Cd stress. Conversely, GSH@MSN-CS showed comparable effects to GSH alone. Foliar-applied GSH@MSN-CS and MT@MSN-CS both decreased the Cd transport coefficients from panicle nodes to brown rice by 26.2-53.3%, with MT@MSN-CS demonstrating superior efficiency in reducing Cd concentrations across roots, stems, leaves, panicle nodes, and grains. Metabolomic analysis revealed substantial shifts in rice metabolite profiles following GSH@MSN-CS and MT@MSN-CS treatments. Foliar application of MT@MSN-CS or GSH@MSN-CS may rapidly and effectively activate the primary antioxidant defense system and alleviate membrane lipid peroxidation in rice grown on low-to-moderately Cd-contaminated soils by upregulating amino acid metabolism. The secondary defense mechanism, phenylpropanoid biosynthesis, was reprogrammed to reduce energy expenditure and decrease Cd translocation.