Trimethyltin (TMT), a type of organotin compound, induces neuronal loss in specific brain regions and cognitive impairments. These changes are transient and followed by recovery, thereby indicating a model of transient brain damage. Memantine (MEM) has neuroprotective properties. However, its effects against neurodegeneration during brain injury are inconsistent. The current study aimed to elucidate the effects of early MEM treatment on the outcomes of brain injury. Memantine at a dose of 10 mg/kg was administered for three consecutive days starting immediately after the administration of TMT at a dose of 2.6 mg/kg. We evaluated neuronal loss and cognitive function in the hippocampal dentate gyrus 3 or 7 days after TMT administration. Results showed that MEM had no significant impact on working memory impairment 3 days after TMT administration. However, it significantly worsened cognitive function 7 days after TMT administration. Furthermore, Fluoro-Jade B staining revealed that MEM exacerbated neuronal degeneration induced by TMT administration. Based on these findings, early MEM treatment after TMT administration could exacerbate hippocampal neurodegeneration and cognitive impairment. Therefore, at least in the early stages of brain injury, MEM administration can worsen the prognosis of transient neuronal degeneration.