Manganese (Mn)-induced neurotoxicity has aroused public concerns for many years, but its precise mechanism is still poorly understood. Herein, we report the impacts of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway in mediating neurological effects induced by manganese sulfate (MnSO) exposure in PC12 cells. In this study, cells were treated with MnSO for 24 h in the absence or presence of LY294002 (a special inhibitor of PI3K). We investigated cell viability and apoptosis signals, as well as levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). The mRNA levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-3 were also quantified through real-time quantitative PCR (RT-qPCR); protein levels of serine/threonine protein kinase (Akt) and forkhead box O3A (Foxo3a) were determined by western blot. Increasing of MnSO doses led to decreased SOD, GSH-Px, and CAT activities, while the level of MDA was upregulated. Moreover, cell apoptosis was significantly increased, as the mRNA of Bcl-2 and Caspase-3 was significantly decreased, while Bax mRNA was increased. Phosphorylated Akt (p-Akt) and Foxo3a (p-Foxo3a) were upregulated in a dose-dependent manner. In addition, LY294002 pretreatment reduced the activity of SOD, GSH-Px, and CAT but elevated MDA levels. Meanwhile, LY294002 pretreatment also increased cell apoptosis given the upregulated Bax and Caspase-3 mRNAs and decreased Bcl-2 mRNA. In summary, the PI3K/Akt signaling pathway can be activated by MnSO exposure and mediate MnSO-induced neurotoxicity.