Cadmium (Cd) contamination in soils threatens food security, while cultivating low-Cd-accumulative varieties, coupled with agro-nanotechnology, offers a potential solution to reduce Cd accumulation in crops. Herein, foliar application of selenium nanoparticles (SeNPs) was performed on seedlings of two low-Cd-accumulative wheat (Triticum aestivum L.) varieties grown in soil spiked with Cd at 3 mg/kg. Results showed that foliar application of SeNPs at 0.16 mg/plant (SeNPs-M) significantly decreased the Cd content in leaves of XN-979 and JM-22 by 46.4 and 40.8 %, and alleviated oxidative damage. The wheat leaves treated with SeNPs-M underwent significant metabolic and transcriptional reprogramming. On one hand, four specialized antioxidant metabolites such as LTyrosine, beta-N-acetylglucosamine, D-arabitol, and monolaurin in response to SeNPs in JM-22 and XN-979 is the one reason for the decrease of Cd in wheat leaves. Moreover, alleviation of stress-related kinases, hormones, and transcription factors through oxidative post-translational modification, subsequently regulates the expression of defense genes via Se-enhanced glutathione peroxidase. These findings indicate that combining low-Cd accumulative cultivars with SeNPs spraying is an effective strategy to reduce Cd content in wheat and promote sustainable agricultural development.