Objective: This investigation was designed to analyze the phytochemicals of the ethanolic extracts of grape and guava seeds and to assess their possible ameliorating effects on gentamicin (GM)-induced nephropathy in rats. Material and methods: Sixty-four male Sprague Dawley rats were randomly allocated into eight groups and treated for ten consecutive days as follows: Group 1 (control group) was injected intraperitoneally with saline solution; Groups 2, 3, and 4 received a daily oral dosage of grape seed extract (GrSE, 40 mg/kg b.wt /day, p.o), guava seed extracts (GuSE, 300 mg/ b.wt /day, p.o) or a combination of both, respectively. Group 5 was intoxicated with GM (100 mg/kg/ b.wt /day, i.p). Groups 6, 7, and 8 received an oral dose of GrSE and/or GuSE along with an intraperitoneal injection of GM. Results: Chemical analysis by high-performance liquid chromatography with diode-array detection (HPLC-DAD) showed that the ethanolic extracts of GrSE and GuSE are rich in phenolic compounds such as gallic acid, chlorogenic acid, 3-hydroxycinnamic acid, ferulic acid, caffeic acid, ellagic acid, daidzein, apigenin, syringic acid, naringenin, p- coumaric acid, quercetin, rutin, and vanillic acid. GrSE or GuSE oral administration did not cause any considerable biochemical or histological alterations in the normal rats. Rats treated with GM showed significant elevation in serum concentration of urea and creatinine and a significant reduction in serum levels of total proteins, sodium, and potassium. In contrast, serum alkaline phosphatase activity was significantly elevated. Additionally, GM injection resulted in a significant rise in the serum levels of triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL), and a significant decrement in serum high-density lipoprotein cholesterol (HDL). Furthermore, GM-injected rats displayed a substantial decline in the activity of erythrocyte copper, zinc superoxide dismutase (Cu, Zn-SOD), and blood and renal levels of reduced glutathione (GSH) along with elevation in the renal level of malondialdehyde (MDA). Up-regulation of kidney injury molecule-1 (KIM-1) and nuclear factor kappa B p65 subunit (NF-κB p65) gene expression was also observed in GM-injected rats compared with control. Simultaneous administration of GrSE and/or GuSE with gentamicin attenuated the nephrotoxic effects of GM as indicated by improvement in renal function parameters, normalization of serum electrolytes, restoration of serum lipid profile, reduction in renal lipid peroxidation, enhancement of the antioxidant status and down-regulation of KIM-1 and NF-κB p65 gene expression. The results of histopathological evaluation confirmed these biochemical findings. Conclusion: Treatment with grape and guava seed extracts ameliorated gentamicin-induced nephrotoxicity via hypolipidemic, antioxidant, and anti-inflammatory effects.