Withania somnifera (WS) is utilized in Ayurvedic medicine owing to its central and peripheral beneficial properties. Several studies have accrued indicating that the recreational amphetamine-related drug (+/-)− 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) targets the nigrostriatal dopaminergic system in mice, inducing neurodegeneration and gliosis, causing acute hyperthermia and cognitive impairment. This study aimed to investigate the effect of a standardized extract of W. somnifera (WSE) on MDMA-induced neurotoxicity, neuroinflammation, memory impairment and hyperthermia. Mice received a 3-day pretreatment with vehicle or WSE. Thereafter, vehicle- and WSE-pretreated mice were randomly divided into four groups: saline, WSE, MDMA alone, WSE plus MDMA. Body temperature was recorded throughout treatment, and memory performance was assessed by a novel object recognition (NOR) task at the end of treatment. Thereafter, immunohistochemistry was performed to evaluate in the substantia nigra pars compacta (SNc) and striatum the levels of tyrosine hydroxylase (TH), as marker of dopaminergic degeneration, and of glial fibrillary acidic protein (GFAP) and TMEM119, as markers of astrogliosis or microgliosis, respectively. MDMA-treated mice showed a decrease in TH-positive neurons and fibers in the SNc and striatum respectively, an increase in gliosis and body temperature, and a decrease in NOR performance, irrespective of vehicle or WSE pretreatment. Acute WSE plus MDMA counteracted the modifications in TH-positive cells in SNc, GFAP-positive cells in striatum, TMEM in both areas and NOR performance, as compared to MDMA alone, while no differences were observed as compared to saline. Results indicate that WSE acutely administered in combination with MDMA, but not as pretreatment, protects mice against the noxious central effects of MDMA.