(1) Background: Although Platycodon grandiflorum saponins exhibit many beneficial biological effects in various diseases and conditions, how they protect nerve cells against neurodegenerative diseases and Alzheimer’s disease (AD) pathology is unknown. We investigated whether P. grandiflorum crude saponin (PGS) protects neurons from neurodegeneration caused by amyloid beta (Aβ)-induced oxidative stress. (2) Methods: Hippocampal neuron HT-22 cells were used in the in vitro experiment, and AD mice (5XFAD mice) were used as the in vivo model. Intracellular reactive oxygen species (ROS) was stained with DCF-DA and assessed using fluorescence microscopy. To elucidate the mechanism underlying neuroprotection, intracellular protein levels were assessed by western blotting. In 5XFAD mice, an animal model of AD, nerve damage recovery due to the induction of Aβ toxicity was evaluated by histological analysis. (3) Results: PGS attenuates Aβ-induced neurotoxicity by inhibiting Aβ-induced reactive oxygen species (ROS) production and apoptosis in HT-22 cells. Furthermore, PGS upregulated Nrf2-mediated antioxidant signaling and downregulated NF-κB-mediated inflammatory signaling. Additionally, PGS inhibited apoptosis by regulating the expression of apoptosis-associated proteins. In addition, PGS ameliorated Aβ-mediated pathologies, leading to AD-associated cognitive decline. (4) Conclusions: Taken together, these findings suggest that PGS inhibits Aβ accumulation in the subiculum and cerebral cortex and attenuates Aβ toxicity-induced nerve damage in vitro and in vivo. Therefore, PGS is a resource for developing AD therapeutics.