Background/Aim Apoptosis and oxidative stress have been considered as key events in the pathogenesis of Alzheimer’s disease (AD). Senegenin (Sen), the major and most effective ingredient of Radix Polygalae , which has anti-apoptotic and anti-oxidative effects. The aim of this study was to investigate the anti-apoptotic and anti-oxidant effects of Sen on Aβ 1-42 -induced PC12 cells apoptosis and oxidative stress as well as its possible signaling pathway. Methods Rat pheochromocytoma (PC12) cells were treated by 20 μM Aβ 1-42 and then divided into 5 different treatment groups (Control; Aβ 1-42 20 μM; Aβ 1-42 20 μM + Sen 10 μM; Aβ 1-42 20 μM + Sen 30 μM; Aβ 1-42 20μM + Sen 60 μM). PC12 cells activity was detected by MTT assay. Colony formation assay was performed to assess the clonogenic ability of cells. The cell apoptosis was detected by Annexin-V/PI staining. The pro-apoptotic protein (Bax), anti-apoptotic protein (Bcl-2), anti-oxidative stress factor (HO-1, Nuclear Nrf2, Total Nrf2) and pathway-related protein (Akt, P-Akt, PI3K, P-PI3K) were tested by Western blot. The reactive oxygen species (ROS) level was assessed with a DCFH-DA probe. Results The results indicated that Sen dose-dependently increased cell viability and reduced the number of apoptotic cells. The ratio of P-PI3K/PI3K and P-Akt/Akt increased in a dose-dependent manner under the treatment of Sen, suggesting that Sen might activate the PI3K/Akt signaling pathway. Moreover, Sen upregulates the ratio of Bcl-2/Bax. Further study revealed that Sen can play an antioxidant role in enhancing HO-1, promoting Nrf2 nuclear translocation and reducing ROS accumulation to reduce oxidative stress. Conclusion Sen is effective in inhibiting apoptosis and oxidative stress in Aβ 1-42 -induced PC12 cells, which likely contribute to the development of novel therapies for AD.