Organochalcogens are promising pharmacological agents that possess significant biological activities. Nevertheless, because of the complexity of mammalian models, it has been difficult to determine the molecular pathways and specific proteins that are modulated in response to treatments with these compounds. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging and in vivo live analysis of toxicity. Abundant evidence points to oxidative stress in mediating manganese (Mn)-induced toxicity. In this study we challenged worms with Mn, and investigated the efficacy of inedited selenium- and tellurium- xylofuranosides in reversing and/or protecting the worms from Mn-induced toxicity. In addition, we investigated their putative mechanism of action. First, we determined the lethal dose 50% (LD50) and the effects of the xylofuranosides on various toxic parameters. This was followed by studies on the ability of xylofuranosides to afford protection against Mn-induced toxicity. Both Se- and Te-xylofuranosides increased the expression of superoxide dismutase (SOD-3). Furthermore, we observed that the xylofuranosides induced nuclear translocation of the transcription factor DAF-16/FOXO, which in the worm is known to regulate stress responsiveness, aging and metabolism. These findings suggest that xylofuranosides attenuate toxicity Mn-induced, by regulating the DAF-16/FOXO signaling pathway.