The current study was performed to investigate the nephroprotective efficacy of Spirulina platensis (SP) and the possible benefits of combining SP and ascorbic acid (AA) in protecting against amikacin (AMK)-induced nephrotoxicity in rabbits. Forty-two male New Zealand rabbits were allocated to seven equal groups, receiving (I) normal saline as negative controls, (II) oral SP (500 mg/kg body weight), (III) oral AA (20 mg/kg bw), (IV) intramuscular AMK injection (100 mg/kg bw), (V) AMK plus SP, (VI) AMK plus AA, or (VII) AMK plus SP and AA at the aforementioned doses. The treatments were given once/day for 7 days. Data analysis showed that in comparison to the control group, AMK-intoxicated rabbits showed significant increases (p ≤ 0.05) in serum concentrations of creatinine, uric acid, and urea, as well as renal tissue concentrations of tumor necrosis factor-α [TNF-α], malondialdehyde [MDA], and nitric oxide [NO]. Moreover, significant (p ≤ 0.05) reductions in renal glutathione concentration, antioxidant enzymatic activities (catalase, glutathione peroxidase, and superoxide dismutase), and total antioxidant capacity were noted following AMK intoxication. Treatment by SP ameliorated most of the aforementioned AMK-induced alterations. Although treatment with AA significantly reduced the renal tissue MDA, NO, and TNF-α concentrations, it was not associated with significant ameliorations of AMK-induced changes in the serum concentrations of renal function markers or renal tissue antioxidant parameters. The nephroprotective effects of SP-AA combination were more potent than SP alone in several parameters. In conclusion, SP alone or in combination with AA minimized the nephrotoxic effects of AMK through their antioxidant and anti-inflammatory activities.