Cadmium (Cd), an environmental toxin, may cause neurological disorders. We studied the role and activation mechanism of FoxO3a in Cd-induced oxidative stress. In addition to oxidative stress, Cd activated the antioxidant defense system in neuronal cells. Furthermore, by using Western blot and confocal microscopy, we found that Cd induced nuclear expression of FoxO3a. Importantly, knockdown of FoxO3a significantly suppressed its target SOD2 protein expression and elevated the level of intracellular ROS, ultimately reducing cell viability in Cd-exposed neuronal cells. These results suggest the protective effect of FoxO3a is associated with oxidative stress resistance. Then, we investigated the activation mechanism of FoxO3a. Our results indicate that the nuclear expression of FoxO3a by Cd may be independent of Akt, which is generally regarded as an important negative regulator of FoxO3a. Furthermore, we found that p38 regulated the nuclear expression of FoxO3a in Cd-exposed cells. Finally, we demonstrate that the p38-FoxO3a pathway inhibits Cd-induced oxidative stress. These signaling molecules may be used as a novel biological marker of Cd-induced oxidative stress and provide potential therapeutic approaches for it.