Oxidative stress and overproduction of free radicals have been reported to be a major pathological hallmark of neurodegenerative diseases. Samultang has been known as a beneficial agent to treat liver disease and cardiovascular diseases. However, the anti-oxidant activities and neuro-protective effects of Samultang against oxidative stress still have not been evaluated yet. The aim of the present study was to investigate the anti-oxidant and protective effects of Samultang and its four herbal plants, Paeonia lactiflora (PL), Ligusticum striatum (LS), Rehmannia glutinosa (RG), and Angelica gigas (AG), in vitro system and in SH-SY5Y neuronal cells. The extracts of Samultang strongly increased the radical scavenging activities of 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical (·OH), and nitric oxide (NO) in a concentration-dependent manner. Furthermore, we investigated the protective effects of Samultang on cellular damage against oxidative stress induced by hydrogen peroxide (HO) in SH-SY5Y cells. Treatment with Samultang alleviated the oxidative stress from HO by increasing the cell viability and decreasing the intracellular reactive oxygen species levels. Based on these results, we further investigated the radical scavenging effects of PL, LS, RG, and AG. In our results, PL had the highest DPPH, ·OH, and NO radical scavenging activities. Thus, PL has a crucial role in Samultang, which has anti-oxidative and neuro-protective effects. The present research suggests that Samultang and PL have protective roles against oxidative stress from HO-induced neuronal cell death.