The kidney is the organ most vulnerable to nephrotoxic drugs such as gentamicin. Nephrotoxicity is a rapid deterioration of kidney function due to various factors. Gentamicin causes nephrotoxicity, which was manifested by an increase in serum kidney biomarkers. Asparagus africanus is one of the ethnomedicinal plants used as traditional medicine for treating various ailments, including kidney disease in Ethiopian society. Thus, the aim of this study is to evaluate the nephroprotective effect of A. africanus root extract on gentamicin-induced nephrotoxicity. Using maceration techniques, 100 g of dried plant powder was extracted in 1 L of ethanol. The physicochemical screening of plant extracts revealed the presence of flavonoids, phenols, tannins, saponins, and steroids. The nephroprotective activity of A. africanus crude extract was evaluated on male Swiss albino mice. The crude ethanolic extract at 200 and 400 mg/kg doses showed strong nephroprotective effects by restoring biomarkers such as creatinine, uric acid, and blood urea nitrogen, which were damaged by gentamicin (
p
<
0.05
) in a dose-dependent manner. The mice treated with higher doses (400 mg/kg) had a comparable nephroprotective effect compared to the positive control group (200 mg/kg silymarin;
p
>
0.05
). The histopathology of the control group showed normal glomeruli, normal parenchyma, distal convoluted, and no tubular damage. The toxicant-induced group showed damage to glomeruli and inflammatory infiltration. Therefore, A. africanus root extract has a nephroprotective activity by retarding the gentamicin toxicity in male Swiss albino mice.