Propionic acid (PRA) is used as a food preservative. This study was aimed to investigate the neuroprotective effect of acetyl-l-carnitine (ALC) and nano-Coenzyme Q (N-CoQ) on brain intoxication induced by PRA in rats. Rats were divided into five groups: group I: control; group II: received PRA; group III: received ALC; group IV: received N-CoQ; and group V: received ALC and N-CoQ for 5 days. The antioxidants in question markedly ameliorated serum interleukin-1β and tumor necrosis factor-α, and brain NO, lipid peroxide, glutathione, and superoxide dismutase levels as well as protein expression of brain-derived neurotrophic factor (BDNF) and P-cyclic-AMP response element-binding protein (CREB) that were altered by a toxic dose of PRA, as well as histopathological alterations, including improvement of the cerebellum architecture. Interestingly, the combination therapy of ALC and N-CoQ achieved the most neuroprotective effect compared with monotherapies. The current study established that N-CoQ is considered as a useful tool to prevent brain injury induced by PRA. BDNF and CREB proteins are involved in both PRA neurotoxicity and treatment.© 2020 Wiley Periodicals, Inc.