<p>The objective of the present review is to discuss the protective effects of SeNPs against metal toxicity with special emphasis on the underlying mechanisms and efficacy of SeNPs in comparison to other Se species. In vivo and in vitro studies show that SeNPs mitigate the adverse effects of metal(loid)s (cadmium, lead, arsenic, aluminum, etc.), metal nanoparticles (silver, cobalt), as well as platinum-based agent cisplatin in brain, liver, kidneys, heart, intestine, and gonads. SeNPs substantially reduce toxic metal accumulation in the organism, thus attenuating their toxicity. In metal-exposed animals, SeNPs enhance the biosynthesis of selenoproteins (including GPX4) and up-regulate Nrf2 signaling, thus inhibiting oxidative stress and ferroptosis. Anti-inflammatory effect of SeNPs was shown to be mediated by inhibition of NF-κB and MAPKs, as well as activation of PI3K/Akt signaling. Inhibition of metal-induced endoplasmic reticulum stress and improvement of autophagy also underlies the protective effects of SeNPs. Neuroprotective effects of SeNPs were shown to be mediated by inhibition of metal-induced increase in amyloid β and Tau protein accumulation and aggregation. The majority of studies show that SeNPs possess stronger protective effect against metal toxicity compared to sodium selenite or organoselenium compounds. Furthermore, the beneficial effects of SeNPs in metal-exposed animals were significantly increased by combined administration or surface modifications with bioactive molecules. Taken together, these findings show that SeNPs possess protective effects against metal toxicity through a variety of mechanisms, although their potential efficacy in treatment metal intoxication in humans has yet to be determined.</p>