Objective: To evaluate the effect of Heracleum persicum L. against gentamicin-induced nephrotoxicity in rats. Methods: Thirty-six Wistar rats were divided into 6 groups including control (normal saline), gentamicin (80 mg/kg/d for 10 d), Heracleum persicum (750 mg/kg/d), and gentamicin (10 d) + Heracleum persicum extract at three different doses (250, 500, and 750 mg/kg/d for 40 d). Urine creatinine, urea, protein, and albumin levels were determined. In addition, serum urea, creatinine, sodium, potassium, cytokines (TNF-α, IL-1β, IL-6, and IL-10), glutathione peroxidase activity, total antioxidant capacity, kidney malondialdehyde, stereological parameters, and expressions of apoptosis-related genes (p53, Bax, Bcl-2, and caspase-3) were measured. The LD50 of Heracleum persicum extract was determined based on Lorke’s method. Histopathological evaluation was also performed. Results: In addition to decreased urine protein and albumin, and increased creatinine and urea, co-treatment with gentamicin and Heracleum persicum significantly reduced levels of creatinine and urea, and increased sodium and potassium in serum. Heracleum persicum treatment also improved stereological parameters and serum inflammatory cytokines. There was a significant increase in serum glutathione peroxidase activity and total antioxidant capacity as well as a reduction in malondialdehyde level. Furthermore, treatment with Heracleum persicum extracts downregulated p53, caspase-3, and Bax and upregulated Bcl-2 expressions. In histopathological evaluation, Heracleum persicum extracts showed protection against gentamicin-induced renal damages. Conclusions: Heracleum persicum exhibits protective effects against gentamicin-induced structural and functional renal impairments.