Vancomycin (VCM) is a widely used antibiotic known for its efficacy against severe bacterial infections, but its administration is often associated with hematological toxicity. This study investigates the protective effects of pomegranate peel extract (PPE) against VCM-induced hematological alterations in male Albino rats. The GC–MS analysis of PPE revealed 22 bioactive components, with major constituents being (E)-9-Octadecenoic acid methyl ester, methyl 9-cis,11-trans-octadecadienoate, and 9-octadecenoic acid (E)-, collectively contributing to its potent antioxidant and anti-inflammatory properties. Thirty-two adult male Albino rats were divided into four groups, (n=8 each): control, PPE alone, VCM alone, and VCM with PPE. The control group was fed the basal diet; the VCM-injected group received VCM (443.6 mg/kg B.W.) every other day for two weeks; the PPE-treated group which was given the basal diet, and a daily dose of PPE (100 mg/kg B.W.) orally for two weeks; and the VCM combined with PPE- group administered the basal diet, and both VCM (every other day) and PPE (daily). After 14 days, hematological parameters, including RBC count, Hb content, Hct %, MCV, WBC count, and differential leukocyte counts, were evaluated. VCM administration significantly reduced RBC count, Hb content, and Hct %, while increasing MCV and altering leukocyte profiles, indicative of hematological toxicity. PPE co-administration effectively ameliorated these adverse effects, restoring RBC indices and reducing inflammation as evidenced by normalized neutrophil-to-lymphocyte ratios. The findings demonstrate that PPE, rich in bioactive fatty acids and antioxidants, mitigates VCM-induced hematological toxicity. These results suggest that PPE has the potential as a protective agent in clinical settings to counteract the adverse hematological effects of VCM therapy. Further studies are warranted to elucidate the underlying mechanisms and to explore the clinical applications of PPE in managing antibiotic-induced hematological disorders.