Nephropathy is a global health issue that affects more than 20% of the adult population. Nephropathy is expected to be the fifth leading cause of death worldwide over the coming two decades. The introduction of green microalgae in nutrition and therapeutics for their biological activities is increasing. The current study examined the effect of Chlorella sorokiniana on renal health after inducing nephrotoxicity in mice. Preliminary screening of the algal aqueous extract revealed the presence of soluble polyphenols and triterpenoids. Successive intraperitoneal doses of gentamicin were administered to mice to induce nephrotoxicity. Concurrent intraperitoneal doses of the algal extract were administered to the infected mice to evaluate their nephroprotective activity. Two different concentrations of the treatment agent were administered in successive doses to two groups of mice. The tested concentrations were 150 and 300 mg/kg of mouse weight, respectively. The other two groups were either left untreated (normal control) or treated only with antibiotics (negative control). Creatinine, urea, and uric acid levels were analyzed in both serum and urine samples to evaluate the renal health of each animal group. Histochemical examination of the renal tissues was performed to assess the damage and improvement status. In vivo studies revealed a promising and significant nephroprotective activity of C. sorokiniana.