Accumulation of cadmium (Cd) ions in soil is an increasingly acute ecological problem in agriculture production. Selenium nanoparticles (SeNPs) can mediate Cd tolerance in plants; however, the underlying mechanisms remain unclear. Herein, we show that the foliar application of SeNPs improved the adaptive capacity of tomato plants to decrease Cd-induced damage. SeNPs induced more Cd in roots but not in shoots despite greater accumulation of selenium and sulfur in both tissues and high selenate influx. Additionally, SeNPs significantly increased thiol compounds, including glutathione, cysteine, and phytochelatins, contributing to enhanced Cd detoxification. Importantly, SeNPs induced the expression of sulfate transporters 1:3, Sadenosylmethionine 1 and polyamine transporter 3. Then, experiments with mutants of these genes showed that SeNP-reduced Cd stress largely relies on the levels and shoot-to-root transport of selenium/sulfur and polyamines. These findings highlight the potential of SeNPs to improve crop production and phytoremediation in heavy metal-contaminated soils.