Oxidative stress and cytotoxic damage induced by amyloid beta (Aβ) have been considered pivotal in the pathogenesis of Alzheimer's disease (AD) and may represent a target for treatment. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival signal to protect against multiple injuries, and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream target of the PI3K/Akt pathway, can bind to HO-1. Resveratrol, a natural polyphenol derived from grapes, has been widely reported to have diverse antioxidative effects against AD, but the mechanisms have not been fully elucidated. The present study aims to investigate the effects of resveratrol on Aβ1-42-induced cytotoxicity in PC12 cells and to explore the potential mechanisms of these effects. PC12 cells were cultured and treated with Aβ1-42. Oxidative stress was assessed by measuring malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels. After treating with resveratrol at different concentrations (0, 10, 20, 40 μM) and for different durations (24, 48, 72 h), the generation of MDA, GSH, and SOD were detected; cell viability was assessed by MTT assay. The production of reactive oxygen species (ROS) was determined using an ROS Assay Kit. Western blotting was used to detect the protein expression. Our studies showed that pretreatment with resveratrol could reduce Aβ1-42-induced oxidative stress in PC12 cells by inhibiting the generation of MDA and ROS and increasing the production of SOD and GSH. Resveratrol markedly attenuated the Aβ1-42-induced loss in cell viability in PC12 cells in both a dose- and time-dependent manner. More importantly, resveratrol stimulated the activation of HO-1, Nrf2, PI3K, and phosphorylated Akt. Notably, the neuroprotective effects of resveratrol were eliminated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP), Nrf2 small interfering RNA (siRNA), and the PI3K/Akt inhibitor LY294002. Taken together, the findings suggest that the cytoprotection of resveratrol against the cytotoxicity induced by Aβ1-42 in PC12 cells is through the upregulation of HO-1 expression via the activation of the PI3K/AKT/Nrf2 intracellular signaling pathway, which might provide novel insights for understanding the mechanism of the neuroprotective effect of resveratrol as an anti-AD drug.