Physiological levels of reactive oxygen species (ROS) are required for the proper regulation of biological functions and cell signaling. However, ROS overproduction and inadequate scavenging lead to oxidative stress and consequent damage to macromolecules. Recent evidence has demonstrated the incontrovertible involvement of oxidative stress in the onset and progression of different central nervous system (CNS) disorders, including neurodegenerative events. For instance, redox disbalance together with α-synuclein aggregation and neuroinflammation, contributes to the loss of dopaminergic neurons in the Substantia Nigra pars compacta in Parkinson’s disease (PD).The Bromo- and ExtraTerminal-domain (BET) family proteins have recently emerged as key epigenetic players in a variety of pathophysiological processes in the CNS, interacting with acetylated lysines of histones and favoring gene transcription. Interestingly, increasing evidence suggests the critical entanglement of BET proteins in the transcription of genes involved in neuroinflammation and redox homeostasis. Nevertheless, the impact of BET modulation on PD is still elusive.Based on these premises, we aimed to evaluate whether pharmacological BET inhibition by JQ1 could ameliorate the parkinsonian phenotype in a rotenone-induced cellular model of PD. Western blot, immunofluorescence and enzymatic activity assays indicated that BET inhibition significantly reduced rotenone-induced oxidative damage, α-synuclein aggregation and mitochondrial dysfunction by activating various molecular pathways involved in cytoprotective defense. Collectively, these effects result in the suppression of cell death and the restoration of neuronal morphology.In conclusion, our data suggest that BET targeting could represent a promising pharmacological approach to counteract PD neuropathology.