This study investigated the effects of different doses of ranolazine in a middle cerebral artery occlusion/reperfusion (MCAO-I/R) model by evaluating histopathological changes and serum Sirtuin 1 (SIRT1), Apela peptide (APELA), and Apelin-13 (APL13) levels. A total of 47 male Sprague Dawley rats (250 ± 20 g) were randomly assigned to five groups: Sham (n = 7), MCAO (n = 10), MCAO+RAN10 (n = 10), MCAO+RAN30 (n = 10), and MCAO+RAN50 (n = 10). MCAO-I/R was induced by transient filament occlusion of the right middle cerebral artery for 90 min followed by reperfusion. Ranolazine was administered intraperitoneally once daily for 21 days in the treatment groups. Serum SIRT1, APELA, and APL13 levels were measured using enzyme-linked immunosorbent assay (ELISA), and brain tissues were evaluated histopathologically for neuronal degeneration and apoptotic cell counts. Histopathological analysis revealed significant neuronal degeneration and increased apoptosis in the MCAO group compared with the Sham group. Ranolazine treatment did not demonstrate significant histopathological improvement compared with the untreated MCAO group. Among the treatment groups, the MCAO+RAN50 group showed higher apoptotic cell counts and lower serum biomarker levels than the other ranolazine-treated groups. Serum SIRT1, APELA, and APL13 levels were lowest in the MCAO+RAN50 group, with selected pairwise differences reaching statistical significance. Under the present experimental conditions, clear evidence of neuroprotection could not be demonstrated. None of the ranolazine-treated groups showed significant histopathological improvement compared with the untreated MCAO group. These findings indicate that higher-dose ranolazine was not associated with neuroprotection under the conditions of this study. However, given the limited sample size, absence of infarct volume analysis, lack of neurological functional assessment, and absence of tissue-level molecular validation, further studies are required to clarify the biological significance and potential clinical relevance of the observed biomarker changes.