The . is a common traditional Chinese medicine. However, its aerial part is currently not widely studied and used. Therefore, we aimed to investigate the neuroprotective effects of total flavonoids in aerial stems and leaves of Fisch. (GSF) by an LPS-induced HT-22 cell model and an () model. In this study, cell apoptosis was evaluated by CCK-8 and Hoechst 33258 staining in LPS-induced HT-22 cells. Meanwhile, ROS level, mitochondrial membrane potential (MMP), and Ca level were detected by the flow cytometer. , was also investigated the effect of GSF on lifespan, spawning, and paralysis. Moreover, the survival of to oxidative stimuli (juglone and HO), and the nuclear translocation of DAF-16 and SKN-1 were evaluated. The results showed that GSF could inhibit LPS-induced HT-22 cell apoptosis. Moreover, GSF decreased the levels of ROS, MMP, Ca, and malondialdehyde (MDA) and increased the activities of SOD and CAT in HT-22 cells. Furthermore, GSF did not affect the lifespan and laying of eggs of N2. However, it delayed paralysis in CL4176 in a dose-dependent manner. Meanwhile, GSF increased the survival rate of CL2006 after juglone and HO treatment, increased SOD and CAT, and decreased MDA levels. Importantly, GSF promoted the nuclear translocation of DAF-16 and SKN-1 in TG356 and LC333, respectively. Taken together, GSF can play a protective role in neuronal cells by inhibiting oxidative stress.