The underlying glial-neuromodulating ability of grape-derived polyphenolic extracts and chemicals is highlighted in this study. Thirty healthy-aged (10 weeks) BALB/c strain mice were simply classified into five groups (6 albino mice per group); Group I (the aged group) was fed a balanced diet, whereas Group II received 200 mg/kg of Black GSE, Group III received 400 mg/kg of Black GSE, Group IV received 200 mg/kg of Red GSE, and Group V obtained 400 mg/kg of Red GSE. The study lasted roughly four weeks, and all treatments were administered as a single daily dose via oral gavage every two days, with the third day off. The brains were carefully dissected and preserved in a 10% paraformaldehyde solution. Morphometric assessment and the immunohisto-chemical analysis were performed for the Primary S100B and CD68KP1 antibodies. Mean values for cell number and nucleus size were calculated for each type of cell including; astrocytes, microglia, and oligodendrocyte with small and large neurons by S100 and CD68pk1 expression. All treated groups, more specifically 400mg/kg of Black and Red GSE significantly played an impact role in reducing the aging damaging effect of S100 in each type of glial (astrocyte, microglia, and oligodendrocyte), and neuron, while increased the scavenging activity of CD68pk1in microglia and neuron that delayed aging and improved brain health in comparison to brain section in the aged group. We concluded that GSE possessed neuroprotective and anti-aging properties by minimizing the adverse effect of S100 and upregulating CD68pk1.