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Perturbation of the protein homeostasis circuit is one of the principal attributes associated with many neurodegenerative disorders, such as Parkinson's disease (PD). This study aimed to explore the neuroprotective effect of roflumilast (ROF), a phosphodiesterase-4 inhibitor, in a rotenone-induced rat model of PD and investigate the potential underlying mechanisms. Interestingly, ROF (1 mg/kg, p.o.) attenuated motor impairment, prevented brain lesions, and rescued the dopaminergic neurons in rotenone-treated rats. Furthermore, it reduced misfolded α-synuclein burden. ROF also promoted the midbrain cyclic adenosine monophosphate level, which subsequently enhanced the 26S proteasome activity and the expression of the 20S proteasome. ROF counteracted rotenone-induced endoplasmic reticulum stress, which was demonstrated by its impact on activating transcription factor 6, glucose-regulated protein 78, and C/EBP homologous protein levels. Moreover, ROF averted rotenone-induced oxidative stress, as evidenced by its effects on the levels of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, reduced glutathione, and lipid peroxides with a significant anti-apoptotic activity. Collectively, this study implies repurposing of ROF as a novel neuroprotective drug owning to its ability to restore normal protein homeostasis. [Display omitted] • Treatment with Roflumilast (ROF) alleviated rotenone-induced motor impairment. • ROF reduced the burden α-Syn aggregates via boosting the 20S proteasome activity. • ROF abrogated the endoplasmic reticulum stress in rotenone-intoxicated rats. • ROF promoted the activity of Nrf2/HO-1 axis in rats. • ROF reversed rotenone-induced oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]