Amyloid β protein (Aβ) causes neurotoxicity and cognitive impairment in Alzheimer’s disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We have previously reported that 2′,3′-dihydroxy-4′,6′-dimethoxychalcone (DDC), a component of green perilla, enhances cellular resistance to oxidative damage through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway. Here, we investigated the effects of DDC on cortical neuronal death induced by Aβ. When Aβ and DDC had been preincubated for 3 h, the aggregation of Aβ was significantly suppressed. In this condition, we found that DDC provided a neuroprotective action on Aβ-induced cytotoxicity. Treatment with DDC for 24 h increased the expression of heme oxygenase-1 (HO-1), and this was controlled by the activation of the Nrf2–ARE pathway. However, DDC did not affect Aβ-induced neuronal death under any of these conditions. These results suggest that DDC prevents the aggregation of Aβ and inhibits neuronal death induced by Aβ, and although it activates the Nrf2–ARE pathway, this mechanism is less involved its neuroprotective effect.