Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. 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. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/FOXO signaling and attenuating oxidative stress.