Estrogen deprivation is linked to a diverse range of functional and histological changes in different body systems, especially kidneys. Hence, this study assesses the potential benefits of fenugreek extract (FGE) in the protection of ovariectomized rats’ renal tissues, even when they received gentamicin treatment (GEN). Forty adult Wistar female rats were assigned into 5 equivalent cohorts. Group 1 (Sham): rats subjected to sham surgery; group 2 (OVX): ovariectomized rats; group 3 (OVX+ FG): ovariectomized rats administered FGE orally with dose 200 mg/kg/day; group 4 (OVX + GEN): ovariectomized rats orally received distilled water for 8 weeks, then were intraperitoneally injected with gentamycin (GEN) with dose of 40 mg /kg/day for 10 days and group 5 (OVX + FG +GEN): ovariectomized rats orally received FGE for 8 weeks and then were intraperitoneally injected with GEN for 10 days concurrently with FGE with the same previous doses. The oral administration of FGE notably decreased serum creatinine, urea, uric acid, Tumor necrosis factor (TNF α ), and Malondialdehyde (MDA), and notably elevated estrogen, Ca, Ph, and Glutathione (GSH), Total antioxidant capacity (TAC), and Interleukin 10 (IL-10) levels in the OVX+ FG and OVX + FG + GEN groups contrasted to the ovariectomized and OVX + GEN groups. Furthermore, it caused an elevation in EGF expression and a decrease in Transforming growth factor beta (TGF-β), Platelet-derived growth factor B (PDGFB), and inducible nitric oxide synthase (iNOS) expressions. The histological changes occurred by the ovariectomy and GEN treatment were improved by FGE. These findings imply that FGE, even in women receiving GEN treatment, is a useful natural treatment for the control of renal abnormalities seen in postmenopausal women.