Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons. In previous our study, an ethanol extract of Brazilian green propolis (EBGP) prevented mutant copper–zinc superoxide dismutase 1 (SOD1^mut)-induced neurotoxicity. This paper aims to reveal the effects of p-coumaric acid (p-CA), an active ingredient contained in EBGP, against SOD1^mut-induced neurotoxicity. We found that p-CA reduced the accumulation of SOD1^mut subcellular aggregation and prevented SOD1^mut-associated neurotoxicity. Moreover, p-CA attenuated SOD1^mut-induced oxidative stress and endoplasmic reticulum stress, which are significant features in ALS pathology. To examine the mechanism of neuroprotective effects, we focused on autophagy, and we found that p-CA induced autophagy. Additionally, the neuroprotective effects of p-CA were inhibited by chloroquine, an autophagy inhibiter. Therefore, these results obtained in this paper suggest that p-CA prevents SOD1^mut-induced neurotoxicity through the activation of autophagy and provides a potential therapeutic approach for ALS.