Background Doxorubicin (DOX) is widely used to treat many human cancers, but significant brain damage limits its clinical application. Objectives To investigate the neuroprotective activity of Terminalia muelleri extract (TME) against DOX-induced neurotoxicity in rats. Materials and methods The first group served as a normal control; the second group served as a positive control which was treated with DOX (2.5 mg/kg; dissolved in saline; intraperitoneal three times/week for 2 weeks,); the third group was treated with TME at a dose of 100 mg/kg; the fourth group was pretreated with TME for 2 weeks and then coadministrated with DOX for other 2 weeks; the fifth and sixth groups were treated with DOX for 2 weeks and then posttreated with two doses of TME (100, 200 mg/kg), respectively, for another 2 weeks. The experiment lasted for 4 weeks; brain tissue samples were harvested for the measurement of toxicity such as oxidative stress, inflammation, apoptosis, neurodegeneration, and histopathological examinations. Results and conclusion DOX-treated animals showed a reduction in glutathione and superoxide dismutase along with a raise in malondialdehyde, nitric oxide, and myeloperoxidase. Also, it caused an increase in caspase-3, indicating an increased propensity for cell death, acetylcholinesterase, extracellular signal-regulated kinase, mammalian target of rapamycin with concomitant decrease in brain-derived neurotrophic factor. However, administration of TME significantly improved oxidative stress alterations, brain-derived neurotrophic factor, and apoptosis. Histological assessments of brain tissues supported the obtained biochemical finding. In conclusion, our findings disclose a potent protective role of TME by activating antioxidant, anti-inflammatory, anti-apoptotic, and neurogenesis effects, which may contribute to the safe use of DOX in cancer treatment.