Symptoms of many neurodegenerative diseases appear later in human life. However, young animal models for penetrating traumatic brain injury (pTBI) have been used to study neurodegenerative diseases and evaluate the efficacy of neuroprotective medicines. Possibly because of this discordance, effective neuroprotective drugs have still not been developed. For patients suffering from pTBI, aging is known to be a significant prognostic factor of mortality. In this study, we aimed to establish a model of aged pTBI animals using Drosophila melanogaster. We successfully generated aged pTBI flies as a new pTBI model showing increased neurodegeneration and higher mortality. To elucidate the mechanism of increased vulnerability in aged pTBI animals, we analyzed the GenBank-deposited transcriptome data of young and aged flies, demonstrating the importance of innate immunity genes for higher mortality in aged pTBI models. We found that in the context of pTBI, normal aging strongly activated the expression of antimicrobial peptide genes and upregulated the nuclear factor-κB gene in the immune deficiency pathway, but not the Toll pathway. Moreover, we found that minocycline increased the survival of young pTBI flies, but not aged pTBI flies. These results suggested that immune system activation under neurodegenerative conditions was involved in normal aging, thereby inhibiting the medicinal efficacy of neuroprotective drugs effective for young flies in aged flies.