Neurodegenerative diseases (NDs) are considered a worldwide health concern that influences a large portion of the aging population. Recently, oxidative stress-mediated pyroptosis has emerged as an innovative therapeutic approach for many NDs including Alzheimer's disease (AD). Therefore, we aimed to examine the potential neuronal anti-pyroptotic activity of vanillin (VA) and to investigate the molecular mechanisms through which VA may ameliorate brain injury induced in rats including its effects on oxidative stress and pyroptosis, which play major roles in the pathogenesis of several NDs including AD. Neurotoxicity was induced in rats by two subcutaneous injections of isoproterenol (ISP) (100 mg kg−1). ISP intervention lasted only two days, where the interval between each injection was 24 hours. After that, the rats were treated with VA (100 mg kg−1 day−1, orally via gavage) for four weeks. ISP provoked neuronal oxidative stress that was characterized by elevated brain contents of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and malonaldehyde (MDA) along with decreased brain contents of sirtuin 1 (SIRT1), glutathione (GSH) and superoxide dismutase (SOD). Furthermore, ISP increased the brain mRNA levels of thioredoxin-interacting protein (TXNIP), nod-like receptor-pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 in addition to the brain contents of TXNIP, NLRP3, ASC, cleaved caspase-1, gasdermin D-N terminal (GSDMD-N), interleukin-18 (IL-18) and interleukin-1β (IL-1β), resulting in pyroptosis. Treatment with VA ameliorated ISP-induced oxidative stress, pyroptosis and histopathological changes via SIRT1/NOX4/ROS/TXNIP/NLRP3 signaling. Our findings suggest a novel therapeutic value for VA in ameliorating neurotoxicity via targeting oxidative stress-mediated pyroptosis.