Introduction: Gentamicin is a widely used aminoglycoside antibiotic, but its nephrotoxic effects significantly limit its therapeutic use, often leading to acute kidney injury (AKI) and hematological disturbances such as anemia. Oxidative stress and inflammation are key mechanisms underlying gentamicin-induced nephrotoxicity (GIN). This study investigates the protective effects of Nefroguard, a novel antioxidant and anti-inflammatory agent, in a rat model of GIN. Objective: To evaluate the protective role of Nefroguard on renal function, hematological parameters, histopathology, and fluid-electrolyte balance in rats with gentamicin-induced nephrotoxicity. Methodology: Randomized controlled animal trial using adult male Wistar rats. Study Duration: The study was conducted over a period of one year (2nd September 2022 to 1st December 2023). Twenty-four adult male Wistar rats were randomized into three groups: Group A (Control), Group B (GIN: Gentamicin 100 mg/kg/day i.p. for 10 days), and Group C (GIN + Nefroguard: Gentamicin + Nefroguard 50 mg/kg/day orally). Parameters assessed included serum urea, creatinine, electrolytes, complete blood count, erythropoietin levels, urine output and osmolarity, and histopathological renal scoring. Data were analyzed using ANOVA with Tukey’s post hoc test (p < 0.05). Results: Gentamicin significantly increased serum urea, creatinine, potassium, and WBCs while reducing sodium, hemoglobin, erythropoietin, and urine output. Nefroguard co-administration significantly reversed these effects, improving renal function markers, electrolyte balance, hematological indices, and urine parameters. Histopathological damage scores were markedly lower in the Nefroguard-treated group compared to the GIN group. Conclusion: Nefroguard demonstrates significant nephroprotective and hematological benefits in gentamicin-Induced nephrotoxicity. Its multidimensional protective profile supports its potential as an adjunct therapy to mitigate drug-induced renal damage and associated systemic effects.