Glycyrrhizic acid (GA) and 18beta-glycyrrhetinic acid (18betaGA) are the bioactive compounds of licorice. The neuroprotective effects of GA and 18betaGA against serum/glucose deprivation and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in PC12 cells were investigated. The intracellular reactive oxygen species (ROS) content, the activity of the antioxidant enzymes of glutathione peroxidase (GPx) and catalase, the mitochondrial membrane potential (MMP), and the mitochondrial Bax/Bcl-2 ratio were determined. PI3K/Akt pathway signaling was also evaluated to study the possible protective mechanism. The results showed that GA treatment decreased the ROS content by elevating the activities of GPx and catalase, leading to a decreased MMP. GA and 18betaGA also lowered the mitochondrial Bax/Bcl-2 ratio and activated PI3K/Akt signal. The results suggest that GA may protect PC12 cells from ischemic injury via modulation of the intracellular antioxidant system and mitochondria-induced apoptosis. Moreover, GA and 18betaGA may modulate the ratio of the mitochondrial Bcl-2 family and influence PI3K/Akt signaling. These results demonstrate the neuroprotective ability of GA and 18betaGA and suggest that the cytotoxicity of 6-OHDA may influence the mitochondrial Bax/Bcl-2 ratio without altering the expression of Bax. This study also suggests a possible compound for treating neural disease and general neuronal health.