Resveratrol has been reported to protect several types of cells against β-amyloid peptide (Aβ) toxicity by scavenging reactive oxygen species (ROS) and inactivating caspase-3. However, other studies found that long-term treatment with resveratrol inhibited cells by inducing ROS generation and activating caspase-3. In the current report, a 48-h incubation of resveratrol at the concentrations of 5 and 10 μM significantly attenuated the viability of PC12 cells and a 12-h pre-incubation of resveratrol did not protect PC12 cells against Aβ exposure (even further inhibited PC12 cells at the concentrations of 10 μM) by acting as a pro-oxidant. Due to the lipophilicity of resveratrol, resveratrol-loaded polymeric micelles basing on amphiphilic block copolymer were developed. Then, the effects of resveratrol-loaded polymeric micelles on the viability and Aβ protection of PC12 cells were investigated. At the equivalent concentrations of 5 and 10 μM resveratrol, a 48-h incubation of resveratrol-loaded nanoparticles did not show toxicity to cells, while 12-h pre-incubation of resveratrol-loaded nanoparticles protected PC12 cells from Aβ-induced damage in a dose dependent manner (1–10 μM) by attenuating intracellular oxidative stress and caspase-3 activity. Further investigations are absolutely needed to evaluate the feasibility and advantages of in vivo applications of resveratrol-loaded nanoparticles.