Oxidative damage contributes to pathogenesis in many neurodegenerative diseases. As the indicator and regulator of oxidative stress, the Nrf2-ARE pathway has been shown dynamic changes and examined for its neuroprotective role in many cases. In this review, we summarize the progress of the Nrf2-ARE pathway in combating toxicity induced from typical misfolded protein aggregates in neurodegenerative diseases, and specifically the effects on the clearance of protein aggregates. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases. •Oxidative damage in neurodegenerative diseases•Dynamic changes and neuroprotection of the Nrf2-ARE pathway•Effects of the Nrf2-ARE pathway on clearance of misfolded protein aggregates